JP6096232B2 - 血管周囲の間葉系前駆細胞に誘導される血管形成 - Google Patents
血管周囲の間葉系前駆細胞に誘導される血管形成 Download PDFInfo
- Publication number
- JP6096232B2 JP6096232B2 JP2015046026A JP2015046026A JP6096232B2 JP 6096232 B2 JP6096232 B2 JP 6096232B2 JP 2015046026 A JP2015046026 A JP 2015046026A JP 2015046026 A JP2015046026 A JP 2015046026A JP 6096232 B2 JP6096232 B2 JP 6096232B2
- Authority
- JP
- Japan
- Prior art keywords
- cells
- stro
- cell
- mpc
- agent according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 210000002901 mesenchymal stem cell Anatomy 0.000 title claims description 161
- 230000033115 angiogenesis Effects 0.000 title description 20
- 210000004027 cell Anatomy 0.000 claims description 239
- 210000001519 tissue Anatomy 0.000 claims description 107
- 102100023126 Cell surface glycoprotein MUC18 Human genes 0.000 claims description 98
- 101000623903 Homo sapiens Cell surface glycoprotein MUC18 Proteins 0.000 claims description 98
- 210000004204 blood vessel Anatomy 0.000 claims description 37
- 210000003205 muscle Anatomy 0.000 claims description 30
- 102000007469 Actins Human genes 0.000 claims description 27
- 108010085238 Actins Proteins 0.000 claims description 27
- 210000003074 dental pulp Anatomy 0.000 claims description 26
- 239000003550 marker Substances 0.000 claims description 24
- 210000003491 skin Anatomy 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 21
- 230000003021 clonogenic effect Effects 0.000 claims description 21
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 claims description 20
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 claims description 20
- 102100035716 Glycophorin-A Human genes 0.000 claims description 16
- 108091005250 Glycophorins Proteins 0.000 claims description 16
- 230000002792 vascular Effects 0.000 claims description 15
- 210000002216 heart Anatomy 0.000 claims description 12
- 210000000988 bone and bone Anatomy 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 102100023543 Vascular cell adhesion protein 1 Human genes 0.000 claims description 9
- 210000004556 brain Anatomy 0.000 claims description 9
- 210000003734 kidney Anatomy 0.000 claims description 9
- 101000935043 Homo sapiens Integrin beta-1 Proteins 0.000 claims description 8
- 102100025304 Integrin beta-1 Human genes 0.000 claims description 8
- 230000003394 haemopoietic effect Effects 0.000 claims description 8
- 210000004185 liver Anatomy 0.000 claims description 8
- 210000000496 pancreas Anatomy 0.000 claims description 8
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 claims description 7
- 210000000952 spleen Anatomy 0.000 claims description 7
- 210000002027 skeletal muscle Anatomy 0.000 claims description 6
- -1 6-19 Proteins 0.000 claims description 5
- 230000002491 angiogenic effect Effects 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 210000004072 lung Anatomy 0.000 claims description 5
- 210000001165 lymph node Anatomy 0.000 claims description 5
- 208000031225 myocardial ischemia Diseases 0.000 claims description 5
- 210000001541 thymus gland Anatomy 0.000 claims description 4
- 210000000515 tooth Anatomy 0.000 claims description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 210000003780 hair follicle Anatomy 0.000 claims description 3
- 210000000936 intestine Anatomy 0.000 claims description 3
- 210000002435 tendon Anatomy 0.000 claims description 3
- 102100022749 Aminopeptidase N Human genes 0.000 claims description 2
- 101000757160 Homo sapiens Aminopeptidase N Proteins 0.000 claims description 2
- 101001078158 Homo sapiens Integrin alpha-1 Proteins 0.000 claims description 2
- 101001078133 Homo sapiens Integrin alpha-2 Proteins 0.000 claims description 2
- 101000994378 Homo sapiens Integrin alpha-3 Proteins 0.000 claims description 2
- 101000994375 Homo sapiens Integrin alpha-4 Proteins 0.000 claims description 2
- 101001015004 Homo sapiens Integrin beta-3 Proteins 0.000 claims description 2
- 102100025323 Integrin alpha-1 Human genes 0.000 claims description 2
- 102100025305 Integrin alpha-2 Human genes 0.000 claims description 2
- 102100032819 Integrin alpha-3 Human genes 0.000 claims description 2
- 102100032818 Integrin alpha-4 Human genes 0.000 claims description 2
- 102100032999 Integrin beta-3 Human genes 0.000 claims description 2
- 102100033010 Integrin beta-5 Human genes 0.000 claims description 2
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 claims description 2
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 claims description 2
- 108091008606 PDGF receptors Proteins 0.000 claims description 2
- 108010069381 Platelet Endothelial Cell Adhesion Molecule-1 Proteins 0.000 claims description 2
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 claims description 2
- 101150052863 THY1 gene Proteins 0.000 claims description 2
- 108010079274 Thrombomodulin Proteins 0.000 claims description 2
- 230000004217 heart function Effects 0.000 claims description 2
- 108010021518 integrin beta5 Proteins 0.000 claims description 2
- 210000003041 ligament Anatomy 0.000 claims description 2
- 210000001525 retina Anatomy 0.000 claims description 2
- 206010002383 Angina Pectoris Diseases 0.000 claims 1
- 206010007559 Cardiac failure congestive Diseases 0.000 claims 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 claims 1
- 206010019280 Heart failures Diseases 0.000 claims 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 claims 1
- 102100020880 Kit ligand Human genes 0.000 claims 1
- 101710177504 Kit ligand Proteins 0.000 claims 1
- 102000003729 Neprilysin Human genes 0.000 claims 1
- 108090000028 Neprilysin Proteins 0.000 claims 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 claims 1
- 102000012607 Thrombomodulin Human genes 0.000 claims 1
- 206010000891 acute myocardial infarction Diseases 0.000 claims 1
- 230000000735 allogeneic effect Effects 0.000 claims 1
- 201000011304 dilated cardiomyopathy 1A Diseases 0.000 claims 1
- 210000001185 bone marrow Anatomy 0.000 description 69
- 230000014509 gene expression Effects 0.000 description 61
- 210000000130 stem cell Anatomy 0.000 description 50
- 238000000034 method Methods 0.000 description 46
- 241000283707 Capra Species 0.000 description 35
- 210000005258 dental pulp stem cell Anatomy 0.000 description 32
- 230000004069 differentiation Effects 0.000 description 27
- 239000006285 cell suspension Substances 0.000 description 26
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 26
- 230000009257 reactivity Effects 0.000 description 25
- 238000000338 in vitro Methods 0.000 description 24
- 230000001332 colony forming effect Effects 0.000 description 21
- 241001465754 Metazoa Species 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 19
- 238000002347 injection Methods 0.000 description 18
- 239000007924 injection Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 238000011282 treatment Methods 0.000 description 18
- 239000000427 antigen Substances 0.000 description 17
- 108091007433 antigens Proteins 0.000 description 17
- 102000036639 antigens Human genes 0.000 description 17
- 238000010186 staining Methods 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 210000004268 dentin Anatomy 0.000 description 16
- 238000010586 diagram Methods 0.000 description 16
- 238000000684 flow cytometry Methods 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 15
- 210000002565 arteriole Anatomy 0.000 description 14
- 230000006872 improvement Effects 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 239000011324 bead Substances 0.000 description 13
- 230000002093 peripheral effect Effects 0.000 description 13
- 239000011780 sodium chloride Substances 0.000 description 13
- 108010047303 von Willebrand Factor Proteins 0.000 description 13
- 229960001134 von willebrand factor Drugs 0.000 description 13
- 230000001464 adherent effect Effects 0.000 description 12
- 238000002826 magnetic-activated cell sorting Methods 0.000 description 12
- 102100036537 von Willebrand factor Human genes 0.000 description 12
- 206010029113 Neovascularisation Diseases 0.000 description 11
- 241000700159 Rattus Species 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- 239000001963 growth medium Substances 0.000 description 11
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 11
- 238000001727 in vivo Methods 0.000 description 11
- 230000006698 induction Effects 0.000 description 11
- 239000002953 phosphate buffered saline Substances 0.000 description 11
- 210000001789 adipocyte Anatomy 0.000 description 10
- 102000029816 Collagenase Human genes 0.000 description 9
- 108060005980 Collagenase Proteins 0.000 description 9
- 101710121996 Hexon protein p72 Proteins 0.000 description 9
- 101710125418 Major capsid protein Proteins 0.000 description 9
- 102100039373 Membrane cofactor protein Human genes 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 9
- 210000000577 adipose tissue Anatomy 0.000 description 9
- 229960002424 collagenase Drugs 0.000 description 9
- 108010007093 dispase Proteins 0.000 description 9
- 238000002955 isolation Methods 0.000 description 9
- 210000005087 mononuclear cell Anatomy 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 230000008439 repair process Effects 0.000 description 9
- 238000000926 separation method Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 8
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 8
- 102000004142 Trypsin Human genes 0.000 description 8
- 108090000631 Trypsin Proteins 0.000 description 8
- 230000027746 artery morphogenesis Effects 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 210000002798 bone marrow cell Anatomy 0.000 description 8
- 230000008045 co-localization Effects 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 210000002808 connective tissue Anatomy 0.000 description 8
- 210000004351 coronary vessel Anatomy 0.000 description 8
- 230000029087 digestion Effects 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 239000012588 trypsin Substances 0.000 description 8
- 230000008901 benefit Effects 0.000 description 7
- 210000002889 endothelial cell Anatomy 0.000 description 7
- 239000012091 fetal bovine serum Substances 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 238000003125 immunofluorescent labeling Methods 0.000 description 7
- 238000011065 in-situ storage Methods 0.000 description 7
- 230000001939 inductive effect Effects 0.000 description 7
- 230000002062 proliferating effect Effects 0.000 description 7
- 230000006496 vascular abnormality Effects 0.000 description 7
- 108010025714 CD146 Antigen Proteins 0.000 description 6
- 102000049932 CD146 Antigen Human genes 0.000 description 6
- 108010024682 Core Binding Factor Alpha 1 Subunit Proteins 0.000 description 6
- 102000015775 Core Binding Factor Alpha 1 Subunit Human genes 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 6
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 102000004067 Osteocalcin Human genes 0.000 description 6
- 108090000573 Osteocalcin Proteins 0.000 description 6
- 239000002771 cell marker Substances 0.000 description 6
- 230000006378 damage Effects 0.000 description 6
- 210000001968 dental pulp cell Anatomy 0.000 description 6
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 6
- 239000003102 growth factor Substances 0.000 description 6
- 230000003834 intracellular effect Effects 0.000 description 6
- 230000002107 myocardial effect Effects 0.000 description 6
- 210000004165 myocardium Anatomy 0.000 description 6
- 210000005036 nerve Anatomy 0.000 description 6
- 210000000963 osteoblast Anatomy 0.000 description 6
- 210000004786 perivascular cell Anatomy 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 210000002460 smooth muscle Anatomy 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 208000018262 Peripheral vascular disease Diseases 0.000 description 5
- 108010004729 Phycoerythrin Proteins 0.000 description 5
- 230000004186 co-expression Effects 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000003511 endothelial effect Effects 0.000 description 5
- 210000003743 erythrocyte Anatomy 0.000 description 5
- 239000007943 implant Substances 0.000 description 5
- 230000000302 ischemic effect Effects 0.000 description 5
- 210000004088 microvessel Anatomy 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 235000015097 nutrients Nutrition 0.000 description 5
- 230000011164 ossification Effects 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 4
- 206010061598 Immunodeficiency Diseases 0.000 description 4
- 241001529936 Murinae Species 0.000 description 4
- 238000010240 RT-PCR analysis Methods 0.000 description 4
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 4
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 238000000149 argon plasma sintering Methods 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 210000001736 capillary Anatomy 0.000 description 4
- 238000012137 double-staining Methods 0.000 description 4
- 230000009977 dual effect Effects 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 4
- 229960005542 ethidium bromide Drugs 0.000 description 4
- 210000002950 fibroblast Anatomy 0.000 description 4
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 4
- 210000003566 hemangioblast Anatomy 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
- 208000028867 ischemia Diseases 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 210000000578 peripheral nerve Anatomy 0.000 description 4
- 239000012679 serum free medium Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 235000019731 tricalcium phosphate Nutrition 0.000 description 4
- 230000002861 ventricular Effects 0.000 description 4
- 230000007998 vessel formation Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 108700039887 Essential Genes Proteins 0.000 description 3
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 3
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 101710160107 Outer membrane protein A Proteins 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102000007365 Sialoglycoproteins Human genes 0.000 description 3
- 108010032838 Sialoglycoproteins Proteins 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 238000000246 agarose gel electrophoresis Methods 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 230000000692 anti-sense effect Effects 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 230000036770 blood supply Effects 0.000 description 3
- 238000010804 cDNA synthesis Methods 0.000 description 3
- 210000000845 cartilage Anatomy 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 210000001612 chondrocyte Anatomy 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 229960003957 dexamethasone Drugs 0.000 description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 3
- 230000035487 diastolic blood pressure Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 210000001105 femoral artery Anatomy 0.000 description 3
- 230000001605 fetal effect Effects 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 210000005260 human cell Anatomy 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 108010082117 matrigel Proteins 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 239000003226 mitogen Substances 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 230000002188 osteogenic effect Effects 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 210000003668 pericyte Anatomy 0.000 description 3
- 230000001023 pro-angiogenic effect Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000001172 regenerating effect Effects 0.000 description 3
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 210000005167 vascular cell Anatomy 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 102000008076 Angiogenic Proteins Human genes 0.000 description 2
- 108010074415 Angiogenic Proteins Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- 102000000503 Collagen Type II Human genes 0.000 description 2
- 108010041390 Collagen Type II Proteins 0.000 description 2
- 208000002330 Congenital Heart Defects Diseases 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 2
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 2
- 108090000380 Fibroblast growth factor 5 Proteins 0.000 description 2
- 102100028073 Fibroblast growth factor 5 Human genes 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 206010061216 Infarction Diseases 0.000 description 2
- 206010048858 Ischaemic cardiomyopathy Diseases 0.000 description 2
- MIJPAVRNWPDMOR-ZAFYKAAXSA-N L-ascorbic acid 2-phosphate Chemical compound OC[C@H](O)[C@H]1OC(=O)C(OP(O)(O)=O)=C1O MIJPAVRNWPDMOR-ZAFYKAAXSA-N 0.000 description 2
- 101150036434 MPC gene Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 208000004210 Pressure Ulcer Diseases 0.000 description 2
- 206010063897 Renal ischaemia Diseases 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000011759 adipose tissue development Effects 0.000 description 2
- 230000003466 anti-cipated effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 108091092328 cellular RNA Proteins 0.000 description 2
- 230000009816 chondrogenic differentiation Effects 0.000 description 2
- 230000002648 chondrogenic effect Effects 0.000 description 2
- 230000009693 chronic damage Effects 0.000 description 2
- 230000005757 colony formation Effects 0.000 description 2
- 238000010293 colony formation assay Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000002689 dentinogenic effect Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 230000005831 heart abnormality Effects 0.000 description 2
- 230000011132 hemopoiesis Effects 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 230000002055 immunohistochemical effect Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000007574 infarction Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- 201000002818 limb ischemia Diseases 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000010016 myocardial function Effects 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 230000005868 ontogenesis Effects 0.000 description 2
- 238000011422 pharmacological therapy Methods 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 230000036573 scar formation Effects 0.000 description 2
- 238000010187 selection method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 210000004927 skin cell Anatomy 0.000 description 2
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 230000008093 supporting effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000004357 third molar Anatomy 0.000 description 2
- 230000005945 translocation Effects 0.000 description 2
- NMWKYTGJWUAZPZ-WWHBDHEGSA-N (4S)-4-[[(4R,7S,10S,16S,19S,25S,28S,31R)-31-[[(2S)-2-[[(1R,6R,9S,12S,18S,21S,24S,27S,30S,33S,36S,39S,42R,47R,53S,56S,59S,62S,65S,68S,71S,76S,79S,85S)-47-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-18-(4-aminobutyl)-27,68-bis(3-amino-3-oxopropyl)-36,71,76-tribenzyl-39-(3-carbamimidamidopropyl)-24-(2-carboxyethyl)-21,56-bis(carboxymethyl)-65,85-bis[(1R)-1-hydroxyethyl]-59-(hydroxymethyl)-62,79-bis(1H-imidazol-4-ylmethyl)-9-methyl-33-(2-methylpropyl)-8,11,17,20,23,26,29,32,35,38,41,48,54,57,60,63,66,69,72,74,77,80,83,86-tetracosaoxo-30-propan-2-yl-3,4,44,45-tetrathia-7,10,16,19,22,25,28,31,34,37,40,49,55,58,61,64,67,70,73,75,78,81,84,87-tetracosazatetracyclo[40.31.14.012,16.049,53]heptaoctacontane-6-carbonyl]amino]-3-methylbutanoyl]amino]-7-(3-carbamimidamidopropyl)-25-(hydroxymethyl)-19-[(4-hydroxyphenyl)methyl]-28-(1H-imidazol-4-ylmethyl)-10-methyl-6,9,12,15,18,21,24,27,30-nonaoxo-16-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29-nonazacyclodotriacontane-4-carbonyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CSSC[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](Cc4ccccc4)NC3=O)[C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N3CCC[C@H]3C(=O)N[C@@H](C)C(=O)N2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)C(C)C)C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1)C(=O)N[C@@H](C)C(O)=O NMWKYTGJWUAZPZ-WWHBDHEGSA-N 0.000 description 1
- NOEMEJJCNDUHJT-UHFFFAOYSA-N 1,3-dimethyl-8-(2-methylpropyl)-7h-purine-2,6-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=C(CC(C)C)N2 NOEMEJJCNDUHJT-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 101100346189 Caenorhabditis elegans mpc-1 gene Proteins 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000004652 Cardiovascular Abnormalities Diseases 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 108010041308 Endothelial Growth Factors Proteins 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100031547 HLA class II histocompatibility antigen, DO alpha chain Human genes 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101100220044 Homo sapiens CD34 gene Proteins 0.000 description 1
- 101000866278 Homo sapiens HLA class II histocompatibility antigen, DO alpha chain Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 1
- 101000801195 Homo sapiens TLE family member 5 Proteins 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 1
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102100026966 Thrombomodulin Human genes 0.000 description 1
- 102000006747 Transforming Growth Factor alpha Human genes 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 1
- 102000056172 Transforming growth factor beta-3 Human genes 0.000 description 1
- 108090000097 Transforming growth factor beta-3 Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 210000000648 angioblast Anatomy 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 238000010805 cDNA synthesis kit Methods 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 229940047120 colony stimulating factors Drugs 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000009989 contractile response Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000002316 cosmetic surgery Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 208000002925 dental caries Diseases 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002592 echocardiography Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000009762 endothelial cell differentiation Effects 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000006862 enzymatic digestion Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 210000003953 foreskin Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 210000004565 granule cell Anatomy 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 208000024348 heart neoplasm Diseases 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 210000000777 hematopoietic system Anatomy 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000056245 human TLE5 Human genes 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 210000004283 incisor Anatomy 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 210000004523 ligament cell Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000007798 limiting dilution analysis Methods 0.000 description 1
- 230000003520 lipogenic effect Effects 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000003287 lymphocyte surface marker Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000006249 magnetic particle Substances 0.000 description 1
- 238000007885 magnetic separation Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 210000001349 mammary artery Anatomy 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000009681 mesenchymal cell proliferation Effects 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- 210000000651 myofibroblast Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000004031 neuronal differentiation Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000004416 odontoblast Anatomy 0.000 description 1
- 210000004248 oligodendroglia Anatomy 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 238000004091 panning Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000005297 pyrex Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000006884 regulation of angiogenesis Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 210000003752 saphenous vein Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000004116 schwann cell Anatomy 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 101150035983 str1 gene Proteins 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229950003937 tolonium Drugs 0.000 description 1
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
- C12N5/0662—Stem cells
- C12N5/0663—Bone marrow mesenchymal stem cells (BM-MSC)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/44—Vessels; Vascular smooth muscle cells; Endothelial cells; Endothelial progenitor cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
- C12N5/0662—Stem cells
- C12N5/0667—Adipose-derived stem cells [ADSC]; Adipose stromal stem cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
- C12N5/0662—Stem cells
- C12N5/0668—Mesenchymal stem cells from other natural sources
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/069—Vascular Endothelial cells
- C12N5/0691—Vascular smooth muscle cells; 3D culture thereof, e.g. models of blood vessels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2500/00—Specific components of cell culture medium
- C12N2500/30—Organic components
- C12N2500/42—Organic phosphate, e.g. beta glycerophosphate
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/10—Growth factors
- C12N2501/11—Epidermal growth factor [EGF]
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/10—Growth factors
- C12N2501/135—Platelet-derived growth factor [PDGF]
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/10—Growth factors
- C12N2501/165—Vascular endothelial growth factor [VEGF]
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/20—Cytokines; Chemokines
- C12N2501/23—Interleukins [IL]
- C12N2501/235—Leukemia inhibitory factor [LIF]
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/30—Hormones
- C12N2501/38—Hormones with nuclear receptors
- C12N2501/39—Steroid hormones
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2506/00—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells
- C12N2506/13—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from connective tissue cells, from mesenchymal cells
- C12N2506/1346—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from connective tissue cells, from mesenchymal cells from mesenchymal stem cells
- C12N2506/1392—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from connective tissue cells, from mesenchymal cells from mesenchymal stem cells from mesenchymal stem cells from other natural sources
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Organic Chemistry (AREA)
- Developmental Biology & Embryology (AREA)
- Cell Biology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Vascular Medicine (AREA)
- Virology (AREA)
- Cardiology (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Materials For Medical Uses (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
間葉系前駆細胞の単離および富化における多数の試みは、これらの細胞が医学的用途を有する可能性があるためになされてきている。Pittinger他(1999)は、骨髄からのクローン原性細胞の増殖を示し、増大させた間葉系幹細胞の調製物を記載している。骨髄からの比較的高い収率を与えるこのような方法の、さらに最近の例は、Simmons他への公開W001/04268中に開示されている。これらの報告されている間葉系細胞はいずれも、血管形成をもたらすことができる血管系統の細胞を再生することができる細胞として示されることはなかった。
しかしながら今日まで、in vivoで血管組織を形成することができる単離された間葉系前駆細胞の例は存在していない。
修復の必要のあるヒト対象中の損傷組織を修復する方法であって、
(a)MPCの富化した集団を得ること、および
(b)有効量のMPCの富化した集団と前記対象の損傷組織を接触させることを含む方法に属すると言うことができる。
修復の必要のあるヒト対象中の損傷組織を修復する方法であって、
(a)培養物中で請求項41に記載の増大したMPCを増殖させること、および
(b)有効量の増殖した細胞と前記対象の損傷組織を接触させることを含む方法に属すると言うことができる。
第五の態様の第一形では、本発明は、心臓血管形成を誘導する際に使用するための組成物であって、間葉系前駆細胞(MPC)の集団を薬剤として許容可能な担体中に含み、前記MPCが血管周囲マーカーを有し血管前駆細胞である組成物
に属すると言うことができる。
(実施例1)
前駆細胞の単離および増殖
皮膚、毛包、骨髄、腸、脳、膵臓、およびさらに近年では歯髄を含めた幾つかの異なる成体組織において同定した幹細胞の適所は、非常に血管新生した部位であることが多い(1)。正常では静止状態の幹細胞集団の維持および制御は、宿主組織の要件に従い局所の微環境によってしっかりと調節されている(2,3)。骨髄および歯髄の支持結合組織はいずれも、骨および象牙質の周囲の鉱化構造を含めた、それらの各々の微環境を非常に忠実に再生することができる、高い増殖能力を有する間質幹細胞の集団を含む(4,5)。出生後の生物では、骨髄間質は、造血を促進し制御する、ゆるく織り込まれた、非常に血管新生した組織として存在する(6-8)。多くの組織がそれらの再生能力を失うか、あるいはそれらの再生能力が低下したとき、成体の骨髄は造血間葉系組織を連続的に再生する能力を保持しており、隣接する骨表面の再構築を担う(9,10)。対照的に、歯の内側の髄室は、鉱化した象牙質に埋没した微小血管網によって浸潤された、非造血の、緻密な繊維状組織からなる(11-13)。歯の成熟後、歯髄は比較的静止した状態になり、カリエスまたは機械的損傷などの障害によって生じた傷ついた象牙質物質に応答する、修復能力においてのみ作用する。
組織サンプル
正常なヒト成人ボランティア由来の腸骨稜由来の骨髄単核細胞(BMMNC)を、the Royal Adealaide Hospital Human Ethics Committeeによって設定されたガイドラインの下で得た。正常なヒトの埋伏した第三大臼歯は、それぞれthe University of Adelaide Dental Clinic Research、the University of Adelaide Human Ethics Committeeによって設定された承認ガイドラインの下で、若い成人から回収した。廃棄済みの完全な厚さの皮膚および末梢脂肪組織を、the Royal Adelaide Hospital Human Ethics Committeeによって設定されたガイドラインの下で、the Skin Cell Engineering Laboratoryからの通常の成形外科手術手順から得た。前に記載したのと同様に、歯髄組織は歯冠および歯根から分離した(4)。歯髄、皮膚および脂肪組織の単細胞懸濁液を、3mg/mlのI型コラゲナーゼ(Worthington Biochem、Freehold、NJ)および4mg/mlのディスパーゼ(Boeliringer Mannheim、GMBH、ドイツ)の溶液中において、1〜3時間37℃での酵素による消化によって調製した。単細胞懸濁液は、70μmストレーナー(Falcon、BD Labware、Franklin Lakes、NJ)に細胞を通過させることによって得た。骨髄、歯髄、皮膚および脂肪の細胞(0.01〜1×105/ウエル)調製物は、次いで以下に記載したような免疫選択、RNA抽出、または6ウエルプレート中での直接的な培養(Costar、Cambridge、MA)に使用した。
単細胞懸濁液を低い平板培養濃度(6ウエルプレート中の3連当たり1,000細胞と10,000細胞の間)で平板培養して、異なる免疫選択細胞分画のコロニー形成効率を評価した。5%のCO2中において37℃で、20のウシ胎児血清、2mML-グルタミン、100μMのL-アスコルビン酸-2-リン酸、100U/mlのペニシリンおよび1μg/mlのストレプトマイシンを補ったα-改変イーグル培地中で、これらの細胞を培養した。第14日の培養物を4%ホルマリンで固定し、次いで0.1%のトルイジンブルーで染色した。50以上の細胞の凝集体を、コロニー形成単位-繊維芽細胞(CFU-F)と同等なクローン原性コロニーとして記録した。
この手順は、他の箇所(25)に記載した手順の変形である。簡潔には、約1×108個のBMMNCを、氷上で1時間、STRO-1陽性細胞の上清(ネズミ抗ヒトBMSSC、IgM)(29)(1/2)と共にインキュベートした。次いで細胞をPBS/5%FBSで洗浄し、氷上で45分間、ビオチン化ヤギ抗マウスIgM(μ-鎖特異的; Caltag Laboratories、Burlingame、CA)の1/50希釈液に再懸濁させた。洗浄後、氷上で15分間ストレプトアビジンマイクロビーズ(Miltenyi Biotec、Bergisch Gladbach、F.R.G.)と共に細胞をインキュベートし、次いで製造者の推奨に従いMini MACS磁気カラム(Miltenyi Biotec)で分離した。
STRO-1陽性MACS単離細胞を、氷上で20分間ストレプトアビジン-FITC結合体(1/50; CALTAG Laboratories)と共にインキュベートし、次いでPBS/5%FBSで洗浄した。単色蛍光活性化細胞選別(FACS)は、FACStarPLUSフローサイトメーター(Becton Dickinson、Sunnyvale、CA)を使用して行った。二色FACS分析は、MACS単離STRO-1陽性BMMNCを飽和(1:1)レベルのCC9抗体上清(マウス抗ヒトCD146/MUC-18/Mel-CAM、IgG2a、Dr.Stan Gronthos)と共に、氷上で1時間インキュベートすることによって行った。PBS/5%FBSで洗浄した後、第二の標識ヤギ抗マウスIgG2a(γ-鎖特異的)フィコエリスリン(PE)結合抗体(1/50、CALTAG Laboratories)と共に、氷上で20分間細胞をインキュベートした。FACStarPLUSフローサイトメーターの自動細胞沈着装置(ACDU)を使用して、次いで細胞を選別した。限界希釈アッセイ:ウエル当たり1、2、3、4、5、および10個の細胞を接種、24連、前に記載したのと同様に10日間血清不含培地中で培養(26)。同様に、新たに調製した非分画BMMNCを、氷上で1時間CC9(IgG2a)および3G5(IgM)抗体、またはイソ型適合陰性対照抗体と共にインキュベートした。PBS/5%FBSで洗浄した後、第二の標識ヤギ抗マウスIgG2a(γ-鎖特異的)フィコエリスリン(PE)およびIgM(1/50、CALTAG Laboratories)結合抗体と共に、氷上で30分間細胞をインキュベートした。FACStarPLUSフローサイトメーターを使用して分析する前に、細胞をPBS/5%FBSで洗浄した。それぞれの抗体に関する陽性反応性は、イソ型適合対照抗体の99%より大きい蛍光のレベルとして定義した。
ex vivo増殖させた骨髄MPCの単細胞懸濁液を、トリプシン/EDTA処理によって調製し、次いで非希釈STRO-1上清、または異なる細胞系関連マーカーを同定する抗体(10μg/ml)と共に、氷上で1時間インキュベートした。次いで細胞をPBS/5%FBSで洗浄し、ヤギ抗ネズミIgM-フィコエリスリン(1/50、SouthernBiotechnologies)、ヤギネズミまたは抗ウサギIgG-フィコエリスリン(Caltag Laboratories)のいずれかと共にインキュベートした。細胞内抗原を同定するこれらの抗原用に、細胞内マーカーを染色する前に、細胞調製物を細胞膜に浸透させた。イソ型適合対照抗体を同一の条件下で処理した。フローサイトメトリーによる分析は、COULTER EPICS装置を使用して行った。ドットプロットは、イソ型適合陰性対照抗体を参照しながら、それぞれの系の細胞マーカーに関する蛍光強度のレベルを示すリストモード事象を表す。
ヒト組織切片(μm)をキシレン中で脱ろう化し、段階的エタノールを介してPBSに戻した。凍結組織切片(μm)およびサイトスピン調製物は-20℃において15分間冷たいアセトンで固定し、次いでPBS中で洗浄した。その後これらのサンプルを、30分間1.5%の過酸化水素を含むPBSで処理し、洗浄し、次いで室温で1時間5%の非免疫ヤギ血清を用いて阻害した。室温で1時間一次抗体と共に、サンプルをインキュベートした。使用した抗体:マウス(IgG1およびIgG2a)対照(Caltag、Burlingame、CA);ウサギ(Ig)対照、1A4(抗α-平滑筋アクチン、IgG1)、2F11(抗神経フィラメント、IgG1)、F8/86(ネズミ抗フォンウィルブランド因子、IgG1)(Dako、Carpinteria、CA);STRO-1;CC9(抗CD146);LF-151(ウサギ抗ヒト象牙質シアロ糖タンパク質;Dr.L.Fisher、NIDCR/NIH、MD)。作業用希釈物:ウサギ血清(1/500)、モノクローナル抗体上清(1/2)および精製抗体(10μg/ml)。適切な二次抗体、ビオチン化ヤギ抗マウスIgM、IgG1、IgG2aまたはビオチン化ヤギ抗ウサギ抗体と共に、室温で1時間サンプルをインキュベートすることによって、一回の染色を行った(Caltag Laboratories)。アビジン-ペルオキシダーゼ-複合体および基質を、次いで製造者の教示書に従い加えた(Vectastain ABCキット標準、Vector Laboratories)。サンプルはヘマトキシリンで対比染色し、水溶性培地中に包埋させた。室温で45分間、二次抗体、ヤギ抗マウスIgM-テキサスレッドおよびIgG-FITC(CALTAG Laboratories)を加えることによって、二重蛍光標識を行った。洗浄後、サンプルはVECTASHIELD蛍光包埋剤に包埋させた。
歯髄組織の単細胞懸濁液を、STRO-1(1/2)、CD146(1/2)、または3G5(1/2)に反応性がある抗体と共に、氷上で1時間インキュベートした。細胞はPBS/1%BSAで二回洗浄し、次いでヒツジ抗マウスIgG結合またはラット抗マウスIgM結合磁気Dynabeads(細胞当たり4ビーズ:Dynal、オスロ、ノルウェー)のいずれかと共に、40分間回転式ミキサー上で4℃においてインキュベートした。ビーズと結合した細胞は、製造者の推奨するプロトコルに従いMPC-1磁気粒子濃縮装置(Dynal)を使用して除去した。
ex vivoで増殖させた骨髄のSTRO-1brightMPCの単細胞懸濁液を、トリプシン/EDTA処理によって調製し、次いで200μlのマトリゲルを含む48ウエルプレートに平板培養した。STRO-1brightMPCは、10ng/mlで成長因子PDGF、EGF、VEGFを補った無血清培地(Gronthos他2003)中に、ウエル当たり20,000細胞で平板培養した。5%CO2中での37℃における24時間の培養の後、ウエルを洗浄し、次いで4%パラホルムアルデヒドで固定した。免疫組織化学試験を、前に記載したのと同様にヤギ抗ネズミIgGホースラディッシュペルオキシダーゼ抗体/Vectastainingキットを用いて同定したα-平滑筋アクチンに関して後に行った。
ex vivoで増殖させた脂肪由来のMPCの単細胞懸濁液を、in vitroにおいて骨髄のMPCが鉱化した骨髄を形成するのを誘導することが以前に示された(Gronthos他2003)、10%のFCS、100μMのL-アスコルビン酸-2-リン酸、デキサメタソン10-7Mおよび3mMの無機リン酸を補ったαMEM中で培養した。鉱質の堆積は、陽性フォンコッサ染色によって確認した。以前に記載されたのと同様に(Gronthos他2003)、0.5mMのメチルイソブチルメチルキサンチン、0.5μMのヒドロコルチゾン、および60μMのインドメタシンの存在下で、脂肪形成を誘導した。オイルレッドC染色を使用して、脂質含有脂肪細胞を同定した。記載したのと同様に(Pittenger他、1999)、10ng/mlのTGF-β3で処理した凝集した培養物における、軟骨形成分化を評価した。
前に記載したのと同様に(4)、約5.0×106個のSTRO-1bri/CD146+BMSSCまたはCD146+DPSC由来のex vivoで増殖させた細胞を、40mgのヒドロキシアパタイト/リン酸三カルシウム(HA/TCP)、セラミック粉末(Zimmer Inc、Warsaw、IN)と混合させ、次いで10週齢の免疫無防備状態のベージュマウス(NIH-bg-nu-xid、Harlan Sprague Dawley、Indianapolis、IN)の背表面の皮下に移植した。これらの手順は、承認されている動物プロトコル(NIDCR番号00-113)の仕様書に従い行った。
RNASTAT-60(TEL-TEST Inc.Friendswood TX)を使用して、STRO-1BRT/CD146+選別BMMNC、および対照細胞(3週間10-7Mのデキサメタソンの存在下で増殖させた一次BMSSC培養物)から、全RNAを調製した。第一鎖cDNA合成は、オリゴ-dTプライマーを使用して第一鎖cDNA合成キット(GIBCO BRL、Life Technologies)を用いて行った。第一鎖cDNA(2μl)を、46μlの1XPCRマスター反応混合物(Roche Diagnostics、Gmbh Mannheim、ドイツ)、および10pMolのそれぞれのヒト特異的プライマー対:CBFA1(632bp、および3つの小さな可変スプライシング変異体)(27)、センス5'-CTATGGAGAGGACGCCACGCCTGG-3'[配列番号1]、アンチセンス5'-CATAGCCATCGTAGCCTTGTCCT-3'[配列番号2];オステオカルシン(310bp)(4)、センス5'-CATGAGAGCCCTCACA-3'[配列番号3]、アンチセンス5'-AGAGCGACACCCTAGAC-3'[配列番号4];GAPDH(800bp)(4)センス、5'-AGCCGCATCTTCTTTTGCGTC-3'[配列番号5];アンチセンス5'-TCATATTTGGCAGGTTTTTCT-3'[配列番号6]に加えた。この反応混合物を、PCR Express Hybaid熱循環装置(Hybaid、Franklin、MA)中において、95℃で2分間1サイクル、次いで94℃/(30秒)、60℃/(30秒)、72℃/(45秒)で35サイクル、最後に7分間延長して72℃でインキュベートした。増幅後、それぞれの反応混合物を1.5%アガロースゲル電気泳動によって分析し、臭化エチジウム染色によって目に見える状態にした。
BMSSCおよびDPSCは、血管関連抗原STRO-1およびCD146をin vivoで発現する。
我々は以前に、ヒト骨髄の吸引物質由来の全ての検出可能なクローン原性コロニーを、それらのSTRO-1抗原(25,26)の充分な発現に基づいて単離し富化させるための、磁気活性化細胞選別(MACS)の有効性を実証している。BMSSCをさらに特徴付けるために我々は、STRO-1bri/MACS単離細胞を、MUC-18としても知られる細胞表面抗原CD146を認識する他のモノクローナル抗体、CC9(28)、内皮および平滑筋細胞上に存在するMel-CAMおよびSendo-1と共にインキュベートした。これらの試験によって、CC9が全STRO-1+集団由来のSTRO-1陽性発現分画(STRO-1BRT)と選択的に結合したことを、二色FACS分析によって決定した(図1A)。ポアソンの分布統計を使用したクローニング効率アッセイによって、BMSSCの発生の著しい増大を得て(平板培養した5個のSTRO-1BRT/CD146+細胞当たり1個のコロニー)、非分画骨髄細胞と比較すると、クローン原性コロニー集団の2×103倍の富化を得た(図1B)。STRO-1BRT/CD146-細胞分画中では、コロニー形成を検出することはできなかった(データ示さず)。
本発明の試験では、フローサイトメトリーによる分析によって、細胞表面抗原である3G5が、大部分(54%)の造血骨髄細胞によって充分に発現されたことを明らかにした(図4A)。この観察結果によって、ヒト骨髄の吸引物質から精製したBMSSCの集団を直接単離するための、候補マーカーとしての3G5は除外された。さらに、3G5およびSTRO-1の発現に基づく二重FACS分析は、2つの抗体が同じイソ型を共有していたので可能ではなかった。それにもかかわらず、異なる3G5/CD146FACS選別亜分画に関するin vitroでのコロニー効率アッセイによって、少ない比率(14%)の骨髄クローン原性コロニーのみが、3G5抗原を低いレベルで発現したことを実証した(図4B)。逆に、大部分(63%)のクローン原性DPSC(平板培養した105個の細胞当たり192個のコロニー形成細胞±18.4SE、n=3)は、免疫磁気ビーズ法による選択の後に、3G5+細胞分画中に存在した(図2)。3G5は、ヒト歯髄組織の凍結切片中の周皮細胞に対して、特異的な反応性を示した(図3F)。
本発明の試験は、それらの個体発生および分化能が明らかな2つの間葉系幹細胞の集団は、いずれもそのそれぞれの組織の微小血管と関係がある直接の証拠を与える。
成人ヒト骨髄のMPCは、それらのSTRO-1抗原の高発現およびCD34発現の欠如によって、間質前駆細胞、造血幹細胞および血管芽細胞と異なる。
出生後骨髄は、常在性幹細胞、および血液細胞形成(造血幹細胞)、内皮分化(血管芽細胞)、および結合組織/間質分化(間質前駆細胞/骨髄間質幹細胞/間葉系幹細胞)を担う前駆細胞系の中枢であるようである。我々のグループの近年の研究(Gronthos他、2003 ; ShiおよびGronthos 2003)は、それらのSTRO-1抗原の高発現に基づき、免疫グロブリンスーパーファミリーのメンバー、VCAM-1(CD106)およびMUC-18(CD146)のそれらの同時発現によって、ヒトの多型潜在性の骨髄間葉系前駆細胞(MPC)を初めて精製し特徴付けしている。SimmonsおよびTorok-Storb(1991aおよびb)による初期の研究は、in vitroで接着性コロニーを形成する能力を有する、骨髄由来のSTRO-1+間質前駆細胞も、低レベルではあるが造血幹細胞マーカー、CD34を発現したことを示している。これらの研究は、CD34抗体-補体仲介型の細胞溶解を使用して、骨髄の吸引物質中の高い比率の接着性コロニー形成細胞を排除した(SimmonsおよびTorok-Storb 1991b)。STRO-1抗体はヒトCD34+骨髄細胞を用いたマウスの免疫処置後に生成したが、CD34+/グリコホリン-A+非結合赤血球細胞およびCD34+/CD20+B-リンパ球において、適度なレベルから低いレベルでSTRO-1抗原も発現されるという事実によって、この抗体が生じた可能性があることを記すことは重要である。ここで我々は、精巧な蛍光活性化細胞選別技術を使用して、多型潜在性の成人ヒト骨髄のMPCは高レベルのSTRO-1を発現するが、間質前駆細胞、造血幹細胞および血管芽細胞マーカー(CD34)、リンパ球抗原(CD45)、ならびに非結合赤血球細胞マーカー(グリコホリン-A)に対する発現がない直接の証拠を与える(図6A〜C)。これらのデータは、成人ヒト骨髄由来のMPCは、さらに成熟した間質前駆細胞、造血幹細胞および血管芽細胞とは異なる、新規の幹細胞集団であることを実証する(図7)。
異なるヒト組織中の多型潜在性MPCの同定
異なる組織中のMPCの存在および正確な位置は大部分が知られていないが、MPCがヒト骨髄および歯髄組織中の血管周囲の適所に常在するらしいことを、我々は近年実証している(ShiおよびGronthos 2003)。これらの観察結果は、間葉系幹細胞マーカー、STRO-1、平滑筋および周辺細胞マーカー、CD146、α-平滑筋アクチンおよび周辺細胞特異的マーカー、3G5のそれらの発現に基づき異なるMPC集団を同定し単離するための、免疫組織化学法と免疫選択法の組合せに基づいていた。我々は現在これらの試験を拡大して、心臓、肝臓、腎臓、皮膚、脾臓、膵臓、リンパ節を含めた広くさまざまな組織中の、STRO-1/CD146、STRO-1/α-平滑筋アクチン、および3G5/CD146抗原の同時局在を実証している(図8)。
Strobright細胞は新血管新生(血管形成および動脈形成)を誘導し、虚血心筋組織の機能改善をもたらす。
図15。ラット腫瘍に注射したヒトStrobright細胞の拡大および生存。無胸腺ヌードラットに5分間250Gyを照射して、残存するナチュラルキラー機能を除去し、次いで1×106個のラットグリア芽腫細胞を皮下側面に注射した。移植後2週間で、グリア芽腫細胞腫瘍を500,000個のStrobright細胞、500,000個のStrodim細胞または生理食塩水と共に直接注射し、動物は7日後に殺傷した。Strobright細胞を与えた2/3の腫瘍組織では、ラット、ミトコンドリアではなくヒトに対する特異的反応性を有するモノクローナル抗体を使用するイムノペルオキシダーゼ法による染色によって、注射部位付近の多数のヒト細胞を実証し、中期の拡大および生存を示した。ヒト細胞はStrodim細胞を与えた3つの組織のいずれにおいても検出されず、Strobright細胞はこのin vivoモデル系において生存または複製の利点を有する可能性があることが示唆された(図A参照)。Strobright細胞は、小さな毛細血管および細動脈近くの群中に主に存在した(小矢印)(図B)。さらに、幾つかのヒト細胞が、血管構造中に取り込まれるのが見られた(大矢印)(図C)。これらのデータは、ヒトStrobright細胞は内因性(ラット)血管の新血管新生を誘導する可能性があり、ヒト起源の新しい血管中に取り込まれる可能性があることを示す。
ex vivoで増殖させたヒト骨髄間葉系前駆細胞の免疫表現型分析
我々は以前に、多型潜在性の間葉系前駆細胞(MPC)を、表現型STRO-1bright/VCAM-1(CD106)+またはSTRO-1bright/MUC-18(CD146)+に基づいて成人のヒト骨髄単核細胞から精製することができることを報告した(Gronthos他、2003; ShiおよびGronthos 2003)。MPC集団は、明確な培養条件下においてin vitroで容易に増殖させることができる(Gronthos他、2003)。ここで我々は、それぞれ逆転写ポリメラーゼ連鎖反応(RT-PCR)およびフローサイトメトリーによる分析を使用して、mRNAレベルとタンパク質レベルの両方で異なる細胞系と関係があるマーカーに基づき、ex vivoで増殖させたMPC子孫を特徴付けるデータを示す。
Claims (21)
- 対象の心臓機能を改善するための薬剤であって、マーカーSTRO-1を発現する間葉系前駆細胞(MPC)について富化した細胞集団を含み、前記富化した集団が、クローン原性コロニーを形成することができるMPCを少なくとも0.1%含む、薬剤。
- 前記対象が虚血性心臓疾患、冠状動脈疾患、急性心筋梗塞、うっ血性心不全、心筋症、またはアンギナからなる心臓血管疾患に罹患している、請求項1に記載の薬剤。
- 前記富化した集団が、クローン原性コロニーを形成することができる少なくとも1%のMPCを含む、請求項1または2に記載の薬剤。
- 前記富化した集団が少なくとも0.1%のSTRO-1陽性MPCを含む、請求項1から3のいずれか一項に記載の薬剤。
- 前記富化した集団が少なくとも1%のSTRO-1陽性MPCを含む、請求項1から3のいずれか一項に記載の薬剤。
- 前記細胞の富化した集団が、マーカー3G5、MUC18/CD146およびα-平滑筋アクチンの1つまたは複数に対して陽性である、請求項1から5のいずれか一項に記載の薬剤。
- 前記細胞の富化した集団がマーカーVCAM-1をさらに同時発現する、請求項1から6のいずれか一項に記載の薬剤。
- 前記細胞の富化した集団がTHY-1、VCAM-1、ICAM-1、PECAM-1、CD49a/CD49b/CD29、CD49c/CD29、CD49d/CD29、CD29、CD61、インテグリンβ5、6〜19、トロンボモジュリン、CD1O、CD13、SCF、PDGF-R、EGF-R、IGF-1R、NGF-R、FGF-Rおよびレプチン-R(STRO-2)からなる群から選択されるマーカーの1つまたは複数のいずれかを同時発現する、請求項1から7のいずれか一項に記載の薬剤。
- 前記細胞の富化した集団が造血系統のマーカー:CD34、CD45、およびグリコホリン-Aに陰性である、請求項1から7のいずれか一項に記載の薬剤。
- 前記細胞の富化した集団が、歯、歯髄、皮膚、肝臓、腎臓、心臓、網膜、脳、毛包、腸、肺、脾臓、リンパ節、胸腺、膵臓、骨、靭帯、腱、および骨格筋からなる群の組織に由来する、請求項1から9のいずれか一項に記載の薬剤。
- 前記細胞の富化した集団を、血管新生組織源内の血管周囲の適所から単離する、請求項1から8のいずれか一項に記載の薬剤。
- 前記細胞の富化した集団が、非造血血管新生組織内の血管周囲の適所に由来する、請求項1から8のいずれか一項に記載の薬剤。
- 前記富化した集団を投与前に培養および/または増殖させる、請求項1から12のいずれか一項に記載の薬剤。
- 前記培養および/または増殖した集団が、クローン原性コロニーを形成することができる少なくとも1%のMPCを含む、請求項13に記載の薬剤。
- 前記培養および/または増殖した集団が、少なくとも1%のSTRO-1陽性MPCを含む、請求項13に記載の薬剤。
- 前記培養および/または増殖した集団が、少なくとも10%のSTRO-1陽性MPCを含む、請求項13に記載の薬剤。
- 前記細胞の富化した集団が新しい血管構造を構築する、請求項1から12のいずれか一項に記載の薬剤。
- 前記細胞の富化した集団が新しい血管構造の形成を誘導する、請求項1から12のいずれか一項に記載の薬剤。
- 前記培養および/または増殖した細胞の集団が新しい血管構造の形成を誘導する、請求項13から18のいずれか一項に記載の薬剤。
- 前記細胞が自己由来である、請求項1から19のいずれか一項に記載の薬剤。
- 前記細胞が同種異系源由来である、請求項1から19のいずれか一項に記載の薬剤。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2003901668A AU2003901668A0 (en) | 2003-03-28 | 2003-03-28 | Non-haemopoietic precursor cells |
AU2003901668 | 2003-03-28 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2013169111A Division JP6096082B2 (ja) | 2003-03-28 | 2013-08-16 | 血管周囲の間葉系前駆細胞に誘導される血管形成 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2015110659A JP2015110659A (ja) | 2015-06-18 |
JP6096232B2 true JP6096232B2 (ja) | 2017-03-15 |
Family
ID=31500707
Family Applications (10)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006503989A Pending JP2006521096A (ja) | 2003-03-28 | 2004-03-29 | 脈管周囲の間葉系前駆細胞 |
JP2006503990A Expired - Lifetime JP5721302B2 (ja) | 2003-03-28 | 2004-03-29 | 血管周囲の間葉系前駆細胞に誘導される血管形成 |
JP2010274732A Expired - Lifetime JP6043469B2 (ja) | 2003-03-28 | 2010-12-09 | 脈管周囲の間葉系前駆細胞 |
JP2013122605A Expired - Lifetime JP6188435B2 (ja) | 2003-03-28 | 2013-06-11 | 脈管周囲の間葉系前駆細胞 |
JP2013169111A Expired - Lifetime JP6096082B2 (ja) | 2003-03-28 | 2013-08-16 | 血管周囲の間葉系前駆細胞に誘導される血管形成 |
JP2015046026A Expired - Lifetime JP6096232B2 (ja) | 2003-03-28 | 2015-03-09 | 血管周囲の間葉系前駆細胞に誘導される血管形成 |
JP2015112336A Expired - Lifetime JP6257559B2 (ja) | 2003-03-28 | 2015-06-02 | 脈管周囲の間葉系前駆細胞 |
JP2016204162A Pending JP2017014285A (ja) | 2003-03-28 | 2016-10-18 | 血管周囲の間葉系前駆細胞に誘導される血管形成 |
JP2017110753A Pending JP2017148076A (ja) | 2003-03-28 | 2017-06-05 | 脈管周囲の間葉系前駆細胞 |
JP2018172420A Pending JP2019006814A (ja) | 2003-03-28 | 2018-09-14 | 血管周囲の間葉系前駆細胞に誘導される血管形成 |
Family Applications Before (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006503989A Pending JP2006521096A (ja) | 2003-03-28 | 2004-03-29 | 脈管周囲の間葉系前駆細胞 |
JP2006503990A Expired - Lifetime JP5721302B2 (ja) | 2003-03-28 | 2004-03-29 | 血管周囲の間葉系前駆細胞に誘導される血管形成 |
JP2010274732A Expired - Lifetime JP6043469B2 (ja) | 2003-03-28 | 2010-12-09 | 脈管周囲の間葉系前駆細胞 |
JP2013122605A Expired - Lifetime JP6188435B2 (ja) | 2003-03-28 | 2013-06-11 | 脈管周囲の間葉系前駆細胞 |
JP2013169111A Expired - Lifetime JP6096082B2 (ja) | 2003-03-28 | 2013-08-16 | 血管周囲の間葉系前駆細胞に誘導される血管形成 |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015112336A Expired - Lifetime JP6257559B2 (ja) | 2003-03-28 | 2015-06-02 | 脈管周囲の間葉系前駆細胞 |
JP2016204162A Pending JP2017014285A (ja) | 2003-03-28 | 2016-10-18 | 血管周囲の間葉系前駆細胞に誘導される血管形成 |
JP2017110753A Pending JP2017148076A (ja) | 2003-03-28 | 2017-06-05 | 脈管周囲の間葉系前駆細胞 |
JP2018172420A Pending JP2019006814A (ja) | 2003-03-28 | 2018-09-14 | 血管周囲の間葉系前駆細胞に誘導される血管形成 |
Country Status (14)
Country | Link |
---|---|
US (6) | US7947266B2 (ja) |
EP (4) | EP1613335B1 (ja) |
JP (10) | JP2006521096A (ja) |
CN (4) | CN103202857A (ja) |
AU (7) | AU2003901668A0 (ja) |
CA (4) | CA2520273C (ja) |
DK (1) | DK1613335T3 (ja) |
ES (3) | ES2784378T3 (ja) |
FR (1) | FR20C1036I2 (ja) |
NL (1) | NL301059I2 (ja) |
PL (1) | PL1613335T3 (ja) |
PT (1) | PT1613335E (ja) |
SI (1) | SI1613335T1 (ja) |
WO (2) | WO2004085630A1 (ja) |
Families Citing this family (102)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7514074B2 (en) | 1997-07-14 | 2009-04-07 | Osiris Therapeutics, Inc. | Cardiac muscle regeneration using mesenchymal stem cells |
US20050158289A1 (en) * | 1999-07-07 | 2005-07-21 | Simmons Paul J. | Mesenchymal precursor cell and use thereof in the repair of bone defects and fractures in mammals |
AU2003901668A0 (en) | 2003-03-28 | 2003-05-01 | Medvet Science Pty. Ltd. | Non-haemopoietic precursor cells |
US8062675B2 (en) | 1999-07-07 | 2011-11-22 | Angioblast Systems, Inc. | Mesenchymal precursor cell |
AUPQ147799A0 (en) | 1999-07-07 | 1999-07-29 | Medvet Science Pty. Ltd. | Mesenchymal precursor cell |
US7670628B2 (en) * | 1999-07-07 | 2010-03-02 | Angioblast Systems, Inc. | Mesenchymal precursor cell |
DE602004028803D1 (de) | 2003-02-11 | 2010-10-07 | John E Davies | Vorläuferzellen aus der wharton sulze von humanen nabelschnüren |
CN102827806B (zh) * | 2004-09-24 | 2015-03-11 | 成血管细胞系统公司 | 增强间充质前体细胞(mpc)的增生和/或存活的方法 |
EP2348105B1 (en) * | 2004-09-24 | 2018-10-24 | Mesoblast, Inc. | Multipotential expanded mesenchymal precursor cell progeny (MEMP) and uses thereof |
US8287853B2 (en) | 2005-02-11 | 2012-10-16 | Agency For Science, Technology And Research | Methods of culturing mesenchymal stem cells |
US8178085B2 (en) | 2005-02-11 | 2012-05-15 | Agency For Science, Technology And Research | Methods of proliferating stem cells |
EP3327116A1 (en) | 2005-04-12 | 2018-05-30 | Mesoblast, Inc. | Isolation of adult multipotential cells by tissue non-specific alkaline phosphatase |
EP1909581A4 (en) * | 2005-07-29 | 2008-12-31 | Univ Virginia | STEM CELLS OF ADIPOSE TISSUES, PERIVASCULAR CELLS AND PERICYTES |
EP1780265A1 (en) * | 2005-10-25 | 2007-05-02 | Stiftung CAESAR | Differentiation of stem cells into chondrocytes |
CN101479377A (zh) * | 2005-12-22 | 2009-07-08 | 简·恩尼斯 | 来自冷冻的脐带组织的活细胞 |
KR101507174B1 (ko) | 2006-05-05 | 2015-04-01 | 존 이. 다비스 | 면역 특권 및 조절 전구 세포 |
US20100111910A1 (en) * | 2006-07-12 | 2010-05-06 | Angioblast Systems, Inc. | Treatment of excessive neovascularization |
FR2909559B1 (fr) * | 2006-12-06 | 2012-09-07 | Inst Vaisseaux Et Du Sang | Preparations cellulaires pour une utilisation comme agent stimulant la revascularisation |
WO2008077094A2 (en) * | 2006-12-19 | 2008-06-26 | Children's Medical Center Corporation | Methods for promoting neovascularization |
WO2008104064A1 (en) * | 2007-02-26 | 2008-09-04 | Mount Sinai Hospital | Compositions and methods for treating peripheral vascular diseases |
KR102099285B1 (ko) | 2007-08-06 | 2020-04-10 | 메소블라스트, 아이엔씨. | 생체 내에서 결합 조직을 생성, 복구 및/또는 유지하는 방법 |
US9005599B2 (en) | 2008-04-21 | 2015-04-14 | Tissue Regeneration Therapeutics Inc. | Genetically modified human umbilical cord perivascular cells for prophylaxis against or treatment of biological or chemical agents |
KR101776959B1 (ko) | 2008-06-25 | 2017-09-08 | 메소블라스트, 아이엔씨. | 추간판의 치료 및/또는 재구성 |
JP2011526892A (ja) * | 2008-06-30 | 2011-10-20 | アンジオブラスト システムズ,インコーポレーテッド | 併用療法を使用した眼疾患及び過剰血管新生の治療 |
WO2010011185A1 (en) * | 2008-07-21 | 2010-01-28 | Agency For Science, Technology And Research | Stem cells obtained through in vitro culture with heparan sulfate |
PE20110400A1 (es) | 2008-08-20 | 2011-06-22 | Anthrogenesis Corp | Composiciones mejoradas de celulas y metodos para preparar las mismas |
MX2008014536A (es) * | 2008-11-13 | 2009-01-16 | Internac Para La Terapia Celul | Compuesto de regeneracion celular. |
CN104546912B (zh) | 2008-11-20 | 2019-11-08 | 中胚有限公司 | 用于治疗胰功能异常的方法 |
SG174426A1 (en) | 2009-03-20 | 2011-10-28 | Angioblast Systems Inc | Production of reprogrammed pluripotent cells |
WO2011022071A2 (en) * | 2009-08-20 | 2011-02-24 | The Regents Of The University Of California | Cardiac compositions |
US8628979B2 (en) | 2009-10-21 | 2014-01-14 | Pronota N.V. | MCAM as a biomarker for fluid homeostasis |
WO2011106234A1 (en) | 2010-02-25 | 2011-09-01 | Provasculon, Inc. | Protease-resistant mutants of stromal cell derived factor-1 in the repair of tissue damage |
US8883210B1 (en) | 2010-05-14 | 2014-11-11 | Musculoskeletal Transplant Foundation | Tissue-derived tissuegenic implants, and methods of fabricating and using same |
US9352003B1 (en) | 2010-05-14 | 2016-05-31 | Musculoskeletal Transplant Foundation | Tissue-derived tissuegenic implants, and methods of fabricating and using same |
US10130736B1 (en) | 2010-05-14 | 2018-11-20 | Musculoskeletal Transplant Foundation | Tissue-derived tissuegenic implants, and methods of fabricating and using same |
KR101891260B1 (ko) | 2010-07-02 | 2018-08-24 | 메소블라스트, 아이엔씨. | T-세포 매개된 면역 질환의 치료 |
EP2606121B1 (en) * | 2010-08-19 | 2016-05-11 | The Regents of The University of California | Compositions comrpising perivascular stem cells and nell-1 protein |
CN101985052B (zh) * | 2010-08-31 | 2013-11-06 | 中国人民解放军第二军医大学 | 自动捕获内皮祖细胞促进血管化的皮肤替代物及其构建方法 |
WO2012040408A2 (en) * | 2010-09-23 | 2012-03-29 | Children's Medical Center Corporation | Engineered vascular adipose tissue |
WO2012048275A2 (en) | 2010-10-08 | 2012-04-12 | Caridianbct, Inc. | Configurable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system |
US8834928B1 (en) | 2011-05-16 | 2014-09-16 | Musculoskeletal Transplant Foundation | Tissue-derived tissugenic implants, and methods of fabricating and using same |
JP6091492B2 (ja) * | 2011-05-19 | 2017-03-08 | メゾブラスト,インコーポレーテッド | 肥満および/または代謝症候群を治療する方法 |
KR20180126607A (ko) * | 2011-06-03 | 2018-11-27 | 메소블라스트, 아이엔씨. | 뇌졸중 증상을 치료하는 방법 |
WO2012162754A1 (en) * | 2011-06-03 | 2012-12-06 | Mesoblast, Inc | Methods of treating or preventing neurological diseases |
US10662234B2 (en) | 2011-06-07 | 2020-05-26 | Mesoblast International Sàrl | Methods for repairing tissue damage using protease-resistant mutants of stromal cell derived factor-1 |
KR101786862B1 (ko) | 2011-07-04 | 2017-10-18 | 메소블라스트, 아이엔씨. | 류마티즘성 질환을 치료 또는 예방하는 방법 |
JP6607675B2 (ja) | 2011-07-06 | 2019-11-20 | セル セラピー リミテッド | 中胚葉系列の前駆細胞 |
EP2734618B1 (en) * | 2011-07-20 | 2017-06-14 | Paracelsus Medizinische Privatuniversität Salzburg - Privatstiftung | Pluripotent tendon and ligament perivascular cells |
JP2014529406A (ja) * | 2011-08-29 | 2014-11-13 | セーフガードセル テクノロジー インク. | 血管周囲薬用細胞の単離および治療的使用 |
JP5831059B2 (ja) * | 2011-09-07 | 2015-12-09 | ソニー株式会社 | 光学的測定装置、フローサイトメーター及び光学的測定方法 |
US9177336B2 (en) * | 2011-09-08 | 2015-11-03 | Telefonaktiebolaget L M Ericsson (Publ) | Apparatuses and methods for recommending a path through an information space |
WO2013033777A1 (en) | 2011-09-09 | 2013-03-14 | Mesoblast, Inc | Methods for increasing osteoblastic function |
CN102539736B (zh) * | 2011-12-16 | 2015-04-29 | 北京汉氏联合生物技术有限公司 | 一种cd106阳性细胞、其鉴定、制备方法及应用 |
KR102143255B1 (ko) * | 2012-08-01 | 2020-08-10 | 유나이티드 세러퓨틱스 코오포레이션 | 중간엽 줄기 세포를 사용한 폐동맥 고혈압의 치료 |
WO2014022376A2 (en) | 2012-08-01 | 2014-02-06 | United Therapeutics Corporation | Treatment of pulmonary arterial hypertension with prostacyclin-treated endothelial progenitor cells |
WO2014089623A1 (en) * | 2012-12-12 | 2014-06-19 | Mesoblast, Inc. | Treatment of diseases of endothelial dysfunction and inflammation |
EP2931373B1 (en) | 2012-12-12 | 2019-08-21 | Mesoblast, Inc. | Methods of treating or preventing respiratory conditions |
EP2943069B1 (en) * | 2013-01-09 | 2018-08-15 | United Therapeutics Corporation | Treatment of vasculopathy with prostacyclin and mesenchymal stem cells |
US20150037436A1 (en) | 2013-07-30 | 2015-02-05 | Musculoskeletal Transplant Foundation | Acellular soft tissue-derived matrices and methods for preparing same |
WO2015073913A1 (en) | 2013-11-16 | 2015-05-21 | Terumo Bct, Inc. | Expanding cells in a bioreactor |
WO2015089396A1 (en) * | 2013-12-13 | 2015-06-18 | Mesoblast International Sarl | Methods for repairing tissue damage using protease-resistant mutants of stromal cell derived factor-1 |
US11008547B2 (en) | 2014-03-25 | 2021-05-18 | Terumo Bct, Inc. | Passive replacement of media |
JP6882161B2 (ja) | 2014-04-07 | 2021-06-02 | メゾブラスト・インターナショナル・エスアーエールエル | 改善された幹細胞組成物 |
CA2944703C (en) * | 2014-04-11 | 2023-09-19 | The Administrators Of The Tulane Educational Fund | Cell-surface marker of early msc aging |
US10624930B2 (en) | 2014-06-10 | 2020-04-21 | Mesoblast International Sarl | Treatment of immune disorders |
CN106661552B (zh) * | 2014-07-11 | 2020-07-07 | 玛土撤拉有限公司 | 心脏细胞培养材料 |
WO2016049421A1 (en) | 2014-09-26 | 2016-03-31 | Terumo Bct, Inc. | Scheduled feed |
BR112017012911B1 (pt) | 2014-12-23 | 2021-10-05 | Mesoblast International Sàrl | Método para tratamento de insuficiência cardíaca |
KR102660505B1 (ko) | 2014-12-23 | 2024-04-25 | 메조블라스트 인터내셔널 에스에이알엘 | 진행성 심부전증의 예방 |
AU2016227607B2 (en) | 2015-03-04 | 2021-09-30 | Mesoblast International Sarl | Cell culture method for mesenchymal stem cells |
BR112017023660A2 (pt) | 2015-05-05 | 2018-07-17 | Mesoblast Int Sarl | ensaio de potência |
EP3297694A1 (en) | 2015-05-21 | 2018-03-28 | Musculoskeletal Transplant Foundation | Modified demineralized cortical bone fibers |
WO2017004592A1 (en) | 2015-07-02 | 2017-01-05 | Terumo Bct, Inc. | Cell growth with mechanical stimuli |
US10912864B2 (en) | 2015-07-24 | 2021-02-09 | Musculoskeletal Transplant Foundation | Acellular soft tissue-derived matrices and methods for preparing same |
US11052175B2 (en) | 2015-08-19 | 2021-07-06 | Musculoskeletal Transplant Foundation | Cartilage-derived implants and methods of making and using same |
EP3464565A4 (en) | 2016-05-25 | 2020-01-01 | Terumo BCT, Inc. | CELL EXPANSION |
US11685883B2 (en) | 2016-06-07 | 2023-06-27 | Terumo Bct, Inc. | Methods and systems for coating a cell growth surface |
US11104874B2 (en) | 2016-06-07 | 2021-08-31 | Terumo Bct, Inc. | Coating a bioreactor |
CN106119189B (zh) * | 2016-07-11 | 2020-04-10 | 山东亚大药业有限公司 | 胎儿有核红细胞的分离纯化方法及试剂盒 |
JP7179723B2 (ja) | 2016-10-24 | 2022-11-29 | ユナイテッド セラピューティクス コーポレイション | トレプロスチニルによるmscの免疫調節特性の増強 |
WO2018092769A1 (ja) | 2016-11-15 | 2018-05-24 | 株式会社カネカ | 胎児付属物に由来する間葉系幹細胞を含む細胞集団とその製造方法、及び医薬組成物 |
CN109890398B (zh) * | 2017-02-24 | 2024-01-16 | 玛土撤拉有限公司 | 可用于治疗心脏疾病并含有成纤维细胞的注射用组合物以及用于生产用于治疗用途的成纤维细胞的方法 |
US11624046B2 (en) | 2017-03-31 | 2023-04-11 | Terumo Bct, Inc. | Cell expansion |
EP3656842A1 (en) | 2017-03-31 | 2020-05-27 | Terumo BCT, Inc. | Cell expansion |
EP4137562A1 (en) | 2017-05-04 | 2023-02-22 | Mesoblast International Sàrl | Mesenchymal lineage precursor or stem cells with enhanced immunosuppression |
CN112004923A (zh) | 2017-11-22 | 2020-11-27 | 迈索布拉斯特国际有限公司 | 细胞组合物及治疗方法 |
JP7454379B2 (ja) | 2017-12-28 | 2024-03-22 | 株式会社カネカ | 接着性幹細胞を含む細胞集団とその製造方法、及び医薬組成物 |
CN113557296A (zh) | 2018-10-31 | 2021-10-26 | 迈索布拉斯特国际有限公司 | 造血干细胞的扩增 |
CN109321522A (zh) * | 2018-11-20 | 2019-02-12 | 潍坊市康华生物技术有限公司 | 一种制备牙髓干细胞的方法 |
WO2020141473A1 (en) | 2019-01-02 | 2020-07-09 | Mesoblast International Sárl | Method for treating lower back pain |
EP3906036A1 (en) | 2019-01-03 | 2021-11-10 | Mesoblast International Sàrl | Method for improving visual acuity |
WO2020157660A1 (en) | 2019-01-28 | 2020-08-06 | Mesoblast International Sárl | Method for treating or preventing gastrointestinal bleeding |
JP2022533781A (ja) | 2019-05-23 | 2022-07-25 | メゾブラスト・インターナショナル・エスアーエールエル | 脳梗塞からの機能回復 |
JPWO2020251020A1 (ja) | 2019-06-14 | 2020-12-17 | ||
JP2022543445A (ja) | 2019-08-05 | 2022-10-12 | メゾブラスト・インターナショナル・エスアーエールエル | ウイルスベクターを含む細胞組成物及び処置方法 |
AU2021324483A1 (en) | 2020-08-10 | 2023-04-13 | Mesoblast International Sàrl | Cellular compositions and methods of treatment |
JP2024511064A (ja) | 2021-03-23 | 2024-03-12 | テルモ ビーシーティー、インコーポレーテッド | 細胞捕獲及び増殖 |
WO2023238074A1 (en) | 2022-06-08 | 2023-12-14 | Mesoblast International Sarl | Mesenchymal progenitor cells for enhancing partial reprogramming of target cells |
CN115184246B (zh) * | 2022-09-14 | 2023-07-04 | 天津昂赛细胞基因工程有限公司 | 一种利用cd155评价间充质干细胞生物学效力的方法 |
WO2024121821A1 (en) | 2022-12-09 | 2024-06-13 | Mesoblast International Sarl | Conditioned media and use of the same |
WO2024121820A1 (en) | 2022-12-09 | 2024-06-13 | Mesoblast International Sarl | Pre-licensed composition and cell culture methods |
WO2024121818A1 (en) | 2022-12-09 | 2024-06-13 | Mesoblast International Sarl | Method of treating heart failure in subjects with persistent inflammation |
Family Cites Families (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5486359A (en) * | 1990-11-16 | 1996-01-23 | Osiris Therapeutics, Inc. | Human mesenchymal stem cells |
US5811094A (en) * | 1990-11-16 | 1998-09-22 | Osiris Therapeutics, Inc. | Connective tissue regeneration using human mesenchymal stem cell preparations |
US5226914A (en) * | 1990-11-16 | 1993-07-13 | Caplan Arnold I | Method for treating connective tissue disorders |
US5197985A (en) * | 1990-11-16 | 1993-03-30 | Caplan Arnold I | Method for enhancing the implantation and differentiation of marrow-derived mesenchymal cells |
US5837539A (en) * | 1990-11-16 | 1998-11-17 | Osiris Therapeutics, Inc. | Monoclonal antibodies for human mesenchymal stem cells |
IL107642A0 (en) | 1992-11-20 | 1994-02-27 | Amgen Inc | Progenitor b cell stimulating factor |
US5405772A (en) | 1993-06-18 | 1995-04-11 | Amgen Inc. | Medium for long-term proliferation and development of cells |
US5591625A (en) * | 1993-11-24 | 1997-01-07 | Case Western Reserve University | Transduced mesenchymal stem cells |
US5405722A (en) * | 1993-12-22 | 1995-04-11 | Rca Thomson Licensing Corp. | Method for combined baking-out and sealing of an electrophotographically processed screen assembly for a cathode-ray tube |
US5792453A (en) | 1995-02-28 | 1998-08-11 | The Regents Of The University Of California | Gene transfer-mediated angiogenesis therapy |
AU1119397A (en) * | 1995-11-14 | 1997-06-05 | Regents Of The University Of Minnesota | Ex vivo culture of stem cells |
US5827740A (en) * | 1996-07-30 | 1998-10-27 | Osiris Therapeutics, Inc. | Adipogenic differentiation of human mesenchymal stem cells |
US5980887A (en) * | 1996-11-08 | 1999-11-09 | St. Elizabeth's Medical Center Of Boston | Methods for enhancing angiogenesis with endothelial progenitor cells |
US6335195B1 (en) * | 1997-01-28 | 2002-01-01 | Maret Corporation | Method for promoting hematopoietic and mesenchymal cell proliferation and differentiation |
CA2294944A1 (en) * | 1997-07-03 | 1999-01-14 | Osiris Therapeutics, Inc. | Human mesenchymal stem cells from peripheral blood |
JP4562816B2 (ja) * | 1997-07-14 | 2010-10-13 | オシリス セラピューティクス,インコーポレイテッド | 心筋再生のための間葉幹細胞の使用法および組成物 |
WO1999011287A1 (en) * | 1997-09-04 | 1999-03-11 | Osiris Therapeutics, Inc. | Ligands that modulate differentiation of mesenchymal stem cells |
US6368636B1 (en) * | 1998-03-18 | 2002-04-09 | Osiris Therapeutics, Inc. | Mesenchymal stem cells for prevention and treatment of immune responses in transplantation |
AU4221399A (en) * | 1998-05-29 | 1999-12-13 | Osiris Therapeutics, Inc. | Human cd45+ and/or fibroblast + mesenchymal stem cells |
DE69937888T2 (de) * | 1998-07-31 | 2009-01-02 | Genzyme Corp., Cambridge | Verfahren zur Herstellung mesenchymaler Stammzellen |
WO2000053795A1 (en) * | 1999-03-10 | 2000-09-14 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Adipose-derived stem cells and lattices |
US20050158289A1 (en) * | 1999-07-07 | 2005-07-21 | Simmons Paul J. | Mesenchymal precursor cell and use thereof in the repair of bone defects and fractures in mammals |
AUPQ147799A0 (en) * | 1999-07-07 | 1999-07-29 | Medvet Science Pty. Ltd. | Mesenchymal precursor cell |
US7670628B2 (en) * | 1999-07-07 | 2010-03-02 | Angioblast Systems, Inc. | Mesenchymal precursor cell |
AU2003901668A0 (en) * | 2003-03-28 | 2003-05-01 | Medvet Science Pty. Ltd. | Non-haemopoietic precursor cells |
US8062675B2 (en) * | 1999-07-07 | 2011-11-22 | Angioblast Systems, Inc. | Mesenchymal precursor cell |
WO2001007679A1 (en) | 1999-07-26 | 2001-02-01 | Chemetall Plc | Metal surface treatment |
EP1226233B1 (en) | 1999-08-05 | 2011-06-29 | ABT Holding Company | Multipotent adult stem cells and methods for isolation |
US6645727B2 (en) * | 2000-05-26 | 2003-11-11 | Stemcell Technologies Inc. | Antibody compositions for preparing enriched mesenchymal progenitor preparations |
WO2002007679A2 (en) | 2000-07-21 | 2002-01-31 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Adult human dental pulp stem cells in vitro and in vivo |
EP1491093B1 (en) | 2001-02-14 | 2013-07-31 | ABT Holding Company | Multipotent adult stem cells, sources thereof, methods of obtaining and maintaining same, methods of differentiation thereof, methods of use thereof and cells derived thereof |
FR2827868A1 (fr) * | 2001-07-30 | 2003-01-31 | Bp Chem Int Ltd | Procede et dispositif de fabrication en continu d'un polymere d'alcoylene aromatique |
AUPR703601A0 (en) | 2001-08-15 | 2001-09-06 | Peter Maccallum Cancer Institute, The | Identification and isolation of somatic stem cells and uses thereof |
JP2003052365A (ja) * | 2001-08-20 | 2003-02-25 | Japan Science & Technology Corp | 哺乳動物からの間葉系幹細胞の分離及びその利用方法 |
US20050271639A1 (en) * | 2002-08-22 | 2005-12-08 | Penn Marc S | Genetically engineered cells for therapeutic applications |
JP4061487B2 (ja) * | 2002-11-21 | 2008-03-19 | 始 大串 | 血管新生を目的とする移植材料及びその製造方法 |
US7470538B2 (en) * | 2002-12-05 | 2008-12-30 | Case Western Reserve University | Cell-based therapies for ischemia |
ES2366085T3 (es) * | 2003-04-19 | 2011-10-17 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Células madre postnatales y usos de las mismas. |
CN102827806B (zh) | 2004-09-24 | 2015-03-11 | 成血管细胞系统公司 | 增强间充质前体细胞(mpc)的增生和/或存活的方法 |
EP2348105B1 (en) | 2004-09-24 | 2018-10-24 | Mesoblast, Inc. | Multipotential expanded mesenchymal precursor cell progeny (MEMP) and uses thereof |
GB0812683D0 (en) * | 2008-07-11 | 2008-08-20 | Chalabi Rifat A | Multi-heat zone gasifier |
US7942266B2 (en) * | 2009-04-01 | 2011-05-17 | Lincoln Global, Inc. | Electrode packaging to reduce handling damage |
-
2003
- 2003-03-28 AU AU2003901668A patent/AU2003901668A0/en not_active Abandoned
-
2004
- 2004-03-29 CA CA2520273A patent/CA2520273C/en not_active Expired - Lifetime
- 2004-03-29 EP EP04723937.1A patent/EP1613335B1/en not_active Expired - Lifetime
- 2004-03-29 CN CN2013100425948A patent/CN103202857A/zh active Pending
- 2004-03-29 JP JP2006503989A patent/JP2006521096A/ja active Pending
- 2004-03-29 US US10/551,162 patent/US7947266B2/en active Active
- 2004-03-29 CN CN2004800146987A patent/CN1809632B/zh not_active Expired - Lifetime
- 2004-03-29 DK DK04723937.1T patent/DK1613335T3/da active
- 2004-03-29 EP EP11159624.3A patent/EP2380971B1/en not_active Expired - Lifetime
- 2004-03-29 CA CA2816489A patent/CA2816489C/en not_active Expired - Lifetime
- 2004-03-29 CN CN201310127300.1A patent/CN103224907B/zh not_active Expired - Lifetime
- 2004-03-29 AU AU2004223798A patent/AU2004223798B2/en not_active Expired
- 2004-03-29 ES ES11159624T patent/ES2784378T3/es not_active Expired - Lifetime
- 2004-03-29 CA CA2520390A patent/CA2520390C/en not_active Expired - Lifetime
- 2004-03-29 US US10/551,326 patent/US9169466B2/en active Active
- 2004-03-29 EP EP11155631.2A patent/EP2380969B1/en not_active Expired - Lifetime
- 2004-03-29 AU AU2004224830A patent/AU2004224830B2/en not_active Expired
- 2004-03-29 WO PCT/AU2004/000416 patent/WO2004085630A1/en active Application Filing
- 2004-03-29 ES ES11155631.2T patent/ES2689483T3/es not_active Expired - Lifetime
- 2004-03-29 PL PL04723937T patent/PL1613335T3/pl unknown
- 2004-03-29 ES ES04723937.1T patent/ES2465226T3/es not_active Expired - Lifetime
- 2004-03-29 CA CA2872395A patent/CA2872395A1/en not_active Abandoned
- 2004-03-29 WO PCT/AU2004/000417 patent/WO2004084921A1/en active Application Filing
- 2004-03-29 CN CN2004800147388A patent/CN1822846B/zh not_active Expired - Lifetime
- 2004-03-29 SI SI200432157T patent/SI1613335T1/sl unknown
- 2004-03-29 JP JP2006503990A patent/JP5721302B2/ja not_active Expired - Lifetime
- 2004-03-29 PT PT47239371T patent/PT1613335E/pt unknown
- 2004-03-29 EP EP04723935A patent/EP1613741A4/en not_active Withdrawn
-
2006
- 2006-01-05 US US11/326,736 patent/US9175267B2/en active Active
- 2006-08-22 AU AU2006203627A patent/AU2006203627A1/en not_active Abandoned
- 2006-08-22 AU AU2006203628A patent/AU2006203628A1/en not_active Abandoned
-
2009
- 2009-10-21 AU AU2009227897A patent/AU2009227897B2/en not_active Expired
- 2009-10-21 AU AU2009227881A patent/AU2009227881B2/en not_active Expired
-
2010
- 2010-12-09 JP JP2010274732A patent/JP6043469B2/ja not_active Expired - Lifetime
-
2011
- 2011-05-02 US US13/098,892 patent/US20120082649A1/en not_active Abandoned
-
2013
- 2013-06-11 JP JP2013122605A patent/JP6188435B2/ja not_active Expired - Lifetime
- 2013-08-16 JP JP2013169111A patent/JP6096082B2/ja not_active Expired - Lifetime
-
2015
- 2015-03-09 JP JP2015046026A patent/JP6096232B2/ja not_active Expired - Lifetime
- 2015-06-02 JP JP2015112336A patent/JP6257559B2/ja not_active Expired - Lifetime
- 2015-06-23 US US14/746,960 patent/US10421946B2/en active Active
- 2015-09-30 US US14/871,234 patent/US20160317581A1/en not_active Abandoned
-
2016
- 2016-10-18 JP JP2016204162A patent/JP2017014285A/ja active Pending
-
2017
- 2017-06-05 JP JP2017110753A patent/JP2017148076A/ja active Pending
-
2018
- 2018-09-14 JP JP2018172420A patent/JP2019006814A/ja active Pending
-
2020
- 2020-08-05 NL NL301059C patent/NL301059I2/nl unknown
- 2020-08-06 FR FR20C1036C patent/FR20C1036I2/fr active Active
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6096232B2 (ja) | 血管周囲の間葉系前駆細胞に誘導される血管形成 | |
CN112891374A (zh) | 治疗中风的影响的方法 | |
AU2011253681B2 (en) | Perivascular mesenchymal precursor cell induced blood vessel formation | |
AU2017200149A1 (en) | Perivascular mesenchymal precursor cells |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20150312 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A132 Effective date: 20160215 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20160516 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160721 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A132 Effective date: 20161024 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20170116 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20170215 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6096232 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
EXPY | Cancellation because of completion of term |