KR20230161925A - Composition for inducing proliferation and/or migration of mesenchymal stem cells - Google Patents
Composition for inducing proliferation and/or migration of mesenchymal stem cells Download PDFInfo
- Publication number
- KR20230161925A KR20230161925A KR1020230161226A KR20230161226A KR20230161925A KR 20230161925 A KR20230161925 A KR 20230161925A KR 1020230161226 A KR1020230161226 A KR 1020230161226A KR 20230161226 A KR20230161226 A KR 20230161226A KR 20230161925 A KR20230161925 A KR 20230161925A
- Authority
- KR
- South Korea
- Prior art keywords
- mesenchymal stem
- stem cells
- migration
- compound
- composition
- Prior art date
Links
- 210000002901 mesenchymal stem cell Anatomy 0.000 title claims abstract description 80
- 238000013508 migration Methods 0.000 title claims abstract description 38
- 239000000203 mixture Substances 0.000 title claims abstract description 36
- 230000035755 proliferation Effects 0.000 title claims abstract description 21
- 230000005012 migration Effects 0.000 title claims abstract description 20
- 230000001939 inductive effect Effects 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 230000001737 promoting effect Effects 0.000 claims abstract description 26
- 230000004663 cell proliferation Effects 0.000 claims abstract description 23
- 210000001519 tissue Anatomy 0.000 claims description 18
- 210000001185 bone marrow Anatomy 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- 210000004700 fetal blood Anatomy 0.000 claims description 7
- 210000003205 muscle Anatomy 0.000 claims description 7
- 210000005036 nerve Anatomy 0.000 claims description 7
- 210000001691 amnion Anatomy 0.000 claims description 6
- 210000003491 skin Anatomy 0.000 claims description 6
- 210000003954 umbilical cord Anatomy 0.000 claims description 6
- 210000002826 placenta Anatomy 0.000 claims description 5
- 230000012292 cell migration Effects 0.000 abstract description 21
- 238000002054 transplantation Methods 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 26
- 210000000130 stem cell Anatomy 0.000 description 19
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 14
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 14
- UHWVSEOVJBQKBE-UHFFFAOYSA-N Trimetazidine Chemical compound COC1=C(OC)C(OC)=CC=C1CN1CCNCC1 UHWVSEOVJBQKBE-UHFFFAOYSA-N 0.000 description 14
- 229960004117 capecitabine Drugs 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 229960004190 nomegestrol acetate Drugs 0.000 description 14
- IIVBFTNIGYRNQY-YQLZSBIMSA-N nomegestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 IIVBFTNIGYRNQY-YQLZSBIMSA-N 0.000 description 14
- 229960001177 trimetazidine Drugs 0.000 description 14
- KNZADIMHVBBPOA-UHFFFAOYSA-N dyclonine hydrochloride Chemical compound [Cl-].C1=CC(OCCCC)=CC=C1C(=O)CC[NH+]1CCCCC1 KNZADIMHVBBPOA-UHFFFAOYSA-N 0.000 description 10
- 229960003462 dyclonine hydrochloride Drugs 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 6
- 239000012091 fetal bovine serum Substances 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 238000010609 cell counting kit-8 assay Methods 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
- 229940126657 Compound 17 Drugs 0.000 description 4
- 210000000845 cartilage Anatomy 0.000 description 4
- 229940125797 compound 12 Drugs 0.000 description 4
- -1 olive oil Chemical compound 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- 101150050425 CCC2 gene Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 210000001789 adipocyte Anatomy 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 239000003636 conditioned culture medium Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- 101150108928 CCC1 gene Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 108010053823 Rho Guanine Nucleotide Exchange Factors Proteins 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 229960000385 dyclonine Drugs 0.000 description 2
- BZEWSEKUUPWQDQ-UHFFFAOYSA-N dyclonine Chemical compound C1=CC(OCCCC)=CC=C1C(=O)CCN1CCCCC1 BZEWSEKUUPWQDQ-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 2
- 229960002001 ethionamide Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- VAMXMNNIEUEQDV-UHFFFAOYSA-N methyl anthranilate Chemical compound COC(=O)C1=CC=CC=C1N VAMXMNNIEUEQDV-UHFFFAOYSA-N 0.000 description 2
- 210000000963 osteoblast Anatomy 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 239000000243 solution Substances 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
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- QLPUCCUQFOVDMA-SOFGYWHQSA-N (e)-1-(5-bromo-2-hydroxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one Chemical compound COC1=CC=CC=C1\C=C\C(=O)C1=CC(Br)=CC=C1O QLPUCCUQFOVDMA-SOFGYWHQSA-N 0.000 description 1
- LNEYYODFMSUKGY-UXBLZVDNSA-N (e)-3-(2,4-dimethoxyphenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one Chemical compound COC1=CC(OC)=CC=C1\C=C\C(=O)C1=CC=C(O)C=C1 LNEYYODFMSUKGY-UXBLZVDNSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282817 Bovidae Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WYEJUKQNEBUGJF-UHFFFAOYSA-N C(=O)C1CC(Br)CCC1O Chemical compound C(=O)C1CC(Br)CCC1O WYEJUKQNEBUGJF-UHFFFAOYSA-N 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102000009410 Chemokine receptor Human genes 0.000 description 1
- 108050000299 Chemokine receptor Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 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-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 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
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 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
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- KAZSKMJFUPEHHW-DHZHZOJOSA-N Licochalcone A Chemical compound COC1=CC(O)=C(C(C)(C)C=C)C=C1\C=C\C(=O)C1=CC=C(O)C=C1 KAZSKMJFUPEHHW-DHZHZOJOSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 241001494479 Pecora Species 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
- 241000009328 Perro Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 description 1
- 101710088580 Stromal cell-derived factor 1 Proteins 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 210000001188 articular cartilage Anatomy 0.000 description 1
- 230000008901 benefit Effects 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
- 239000012620 biological material Substances 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 210000003321 cartilage cell Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000002659 cell therapy Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000005482 chemotactic factor Substances 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940047120 colony stimulating factors Drugs 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000036576 dermal application Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000482 effect on migration Effects 0.000 description 1
- 230000000431 effect on proliferation Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N lauric acid triglyceride Natural products CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000013028 medium composition Substances 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- XXXJKBSLNRMHLH-UHFFFAOYSA-N phenyl 4-chlorobenzoate Chemical compound C1=CC(Cl)=CC=C1C(=O)OC1=CC=CC=C1 XXXJKBSLNRMHLH-UHFFFAOYSA-N 0.000 description 1
- BUCUTHKQTIKRHI-UHFFFAOYSA-N phenyl thiophene-2-carboxylate Chemical compound C=1C=CSC=1C(=O)OC1=CC=CC=C1 BUCUTHKQTIKRHI-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000005059 placental tissue Anatomy 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- 230000017423 tissue regeneration 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
- 230000010415 tropism Effects 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
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
-
- 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
-
- 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
- C12N2501/999—Small molecules not provided for elsewhere
Abstract
본 발명은 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물에 관한 것으로, 화합물 1, 2 및 3 중 하나 이상을 포함하는 조성물은 중간엽 줄기세포의 증식 및/또는 이동을 촉진시켜 중간엽 줄기세포의 이식을 통한 치료 효율을 증대시킬 수 있을 것으로 기대된다.The present invention relates to a composition for promoting the proliferation and/or migration of mesenchymal stem cells. The composition comprising one or more of compounds 1, 2, and 3 promotes the proliferation and/or migration of mesenchymal stem cells, thereby promoting mesenchymal stem cell proliferation and/or migration. It is expected that treatment efficiency can be increased through transplantation.
Description
본 발명은 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물에 관한 것이다.The present invention relates to a composition for promoting mesenchymal stem cell proliferation and/or migration.
중간엽 줄기 세포는 다분화능을 가진 기질세포(가슴샘이나 골수 등의 기관에서 그 기능을 담당하는 세포나 조직(유조직)에 둘러싸고 지탱하는 세포)로 조골세포(뼈 세포), 연골세포, 근육세포, 지방세포(골수 지방 조직을 만드는 지방세포)를 포함한 다양한 세포로 분화할 수 있다 (Ankrum 등, 2014).Mesenchymal stem cells are multipotent stromal cells (cells that surround and support cells or tissues (parenchyma) that perform their functions in organs such as the thymus or bone marrow), including osteoblasts (bone cells), cartilage cells, muscle cells, It can differentiate into various cells, including adipocytes (adipocytes that create bone marrow adipose tissue) (Ankrum et al., 2014).
중간엽 줄기 세포는 골수, 혈액, 제대혈과 지방 등과 같은 다양한 조직들로부터 분리해낼 수 있으며, 시험관내 배양 조건에서 대량 증식이 가능하여 윤리적인 문제없이 세포 치료제의 원료 세포로 활용할 수 있다는 장점들을 갖고 있다. 또한, 이들은 손상된 조직 및 염증 부위로 이동할 수 있는 지향성(tropism)을 갖고 있어서 상처 치유에 도움을 주며, 여러 조건에서 면역억제 특성을 보인다.Mesenchymal stem cells can be isolated from various tissues such as bone marrow, blood, cord blood, and fat, and can be proliferated in large quantities under in vitro culture conditions, so they have the advantage of being used as raw cells for cell therapy without ethical problems. . Additionally, they have a tropism that allows them to move to damaged tissues and inflamed areas, helping with wound healing and showing immunosuppressive properties in many conditions.
한편, 중간엽 줄기세포는 백혈구와 같은 혈액세포들보다 손상 조직 및 염증 부위로 이동하는 능력이 미약한 편이다. 중간엽 줄기세포는 손상 조직 및 염증 부위로 이동하는 지향성을 가지고 있으나 이를 위한 핵심적인 부착인자(adhesion ligands)와 케모카인 (chemokine) 수용체들은 상대적으로 소량 발현하고 있으며, 이들마저도 대량 증식을 위한 시험관 내 배양을 하는 동안 점차로 잃어버린다고 보고되었다 (Rombouts 등, 2003). 이들의 고발현을 유도하는 연구들이 많이 수행되었으나 대부분의 연구들이 해당 유전자들을 효율적으로 전달하기 위한 벡터로 바이러스 시스템을 사용하여 인간을 대상으로 하는 임상에 적용하기 힘들다는 단점을 가지고 있다.Meanwhile, mesenchymal stem cells have a weaker ability to migrate to damaged tissues and inflamed areas than blood cells such as white blood cells. Mesenchymal stem cells have a tendency to migrate to damaged tissues and areas of inflammation, but the key adhesion factors and chemokine receptors for this are expressed in relatively small amounts, and even these can be cultured in vitro for mass proliferation. It has been reported that it is gradually lost while doing so (Rombouts et al., 2003). Many studies have been conducted to induce high expression of these genes, but most studies use a viral system as a vector to efficiently deliver the genes, which has the disadvantage of being difficult to apply to human clinical trials.
종래선행기술인 한국공개특허 제2013-0085863호에는 콜로니 자극인자를 포함하는 조성물로 중간엽 줄기세포를 자극, 증식시키고 CXCR4, SDF-1에 의해 조절되는 중간엽 줄기세포의 이동 유도용 조성물이 개시되어 있다. 한국등록특허 제1229819호에는 β-픽스(PIX) 유전자를 포함하는 유전자 전달체를 유효성분으로 포함하는 줄기세포 이동성 개선용 조성물, β-픽스(PIX) 유전자의 발현량을 측정함으로서 줄기세포 이동성을 예측하는 방법 및 줄기세포의 이동성을 개선시키는 신경질환 치료 보조제의 스크리닝 방법이 개시되어 있다. 한국등록특허 제2025474호에는 에티오나마이드(ethionamide)를 포함하는 줄기세포 이동성 향상용 배지 조성물, 및 이의 용도가 기재되어 있으며, 한국등록특허 제1466811호에는 손상된 조직 치료용 이식 조성물 및 손상된 조직 부위로 치료용 세포의 인 비보 이동 유도방법으로, 화학주성인자(예컨대, IL-8 또는 MIP-3α)와 반응시킨 생분해성 지지체를 손상된 위치(예컨대, 관절연골 또는 피부)에 이식하여 조직 재생을 위한 세포의 호밍을 유도/촉진함으로써 손상된 조직을 치료하는 방법이 개시되어 있다. 한국공개특허 제2010-0063696호에는 환자의 혈소판들로 혈소판 용해물을 제조하고, 이를 이용하여 세포 성장 배지를 제조하고, 여기에 중간엽 줄기세포를 증식시키는 점이 기재되어 있다.그러나, 상기 기술들은 본 발명의 구성과 차이가 있으며, 비용과 효과면에서도 중간엽 줄기세포의 증식 및 이동을 촉진하는 본 발명과 차이가 있다.Korean Patent Publication No. 2013-0085863, which is a prior art, discloses a composition containing colony-stimulating factors for stimulating and proliferating mesenchymal stem cells and inducing migration of mesenchymal stem cells regulated by CXCR4 and SDF-1. there is. Korean Patent No. 1229819 describes a composition for improving stem cell mobility that contains a gene carrier containing the β-PIX gene as an active ingredient, and predicts stem cell mobility by measuring the expression level of the β-PIX gene. A method for screening and a screening method for a neurological disease treatment adjuvant that improves the mobility of stem cells is disclosed. Korean Patent No. 2025474 describes a medium composition for improving stem cell mobility containing ethionamide and its use, and Korean Patent No. 1466811 describes a transplant composition for treating damaged tissue and damaged tissue sites. As a method of inducing the in vivo migration of therapeutic cells, a biodegradable scaffold reacted with a chemotactic factor (e.g., IL-8 or MIP-3α) is implanted into a damaged location (e.g., articular cartilage or skin) for tissue regeneration. A method of treating damaged tissue by inducing/promoting cell homing is disclosed. Korean Patent Publication No. 2010-0063696 describes preparing a platelet lysate from a patient's platelets, using this to prepare a cell growth medium, and proliferating mesenchymal stem cells in it. However, the above techniques There is a difference in the composition of the present invention, and it also differs from the present invention in terms of cost and effectiveness, which promotes the proliferation and migration of mesenchymal stem cells.
본 발명의 목적은 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물을 제공하는 데 있다.An object of the present invention is to provide a composition for promoting mesenchymal stem cell proliferation and/or migration.
본 발명은 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물을 제공한다.The present invention provides a composition for promoting mesenchymal stem cell proliferation and/or migration.
본 발명에서 “줄기세포 (stem cells)”란 적합한 환경 및 자극을 통해 각종 세포로 분화할 수 있는 능력을 갖추고 있으며, 자가증식 (self-renewal) 능력을 갖추고 있는 세포를 말한다.In the present invention, “stem cells” refer to cells that have the ability to differentiate into various cells through an appropriate environment and stimulation and have the ability to self-renew.
본 발명에서 “중간엽 줄기세포 (mesenchymal stem cells, MSC)”란 연골, 뼈, 지방, 골수간질, 근육, 신경 등을 만드는데 원조가 되는 세포를 말한다. 중간엽 줄기세포는 다분화능 (multipotency)을 가고, 성인에서는 일반적으로 골수에 머물러 있지만 제대, 제대혈, 골수, 지방, 근육, 신경, 피부, 양막, 태반 등 기타 조직 등에도 존재하는 것으로 알려져 있다.In the present invention, “mesenchymal stem cells (MSC)” refers to cells that assist in creating cartilage, bone, fat, bone marrow stroma, muscle, nerve, etc. Mesenchymal stem cells have multipotency and generally remain in the bone marrow in adults, but are known to exist in other tissues such as the umbilical cord, umbilical cord blood, bone marrow, fat, muscles, nerves, skin, amniotic membrane, and placenta.
상기 중간엽 줄기세포는 제대, 제대혈, 골수, 지방, 근육, 신경, 피부, 양막, 태반 조직 유래인 것일 수 있으나 이에 제한되는 것은 아니며, 그 유래 조직에 관계없이 중간엽 줄기세포의 일반적인 특징인 중간엽 계열 (mesodermal lineage)의 세포 예컨대, 골, 지방 및 연골 등으로 분화할 수 있는 세포라면 본 발명의 범위에 제한 없이 포함될 수 있다. 또한, 상기 중간엽 줄기세포는 동물 유래의 중간엽 줄기세포를 모두 포함하며, 상기 동물은 손상 조직이 발생하여 본 발명의 중간엽 줄기세포를 통해 치료가 가능한 인간을 포함한 모든 동물을 의미할 수 있다. 상기 동물은 인간뿐만 아니라 이와 유사한 증상의 치료를 필요로 하는 소, 말, 양, 돼지, 염소, 낙타, 영양, 개, 고양이 등의 포유동물일 수 있으나, 이에 제한되지는 않는다.The mesenchymal stem cells may be derived from umbilical cord, cord blood, bone marrow, fat, muscle, nerve, skin, amniotic membrane, and placental tissue, but are not limited thereto, and are a general characteristic of mesenchymal stem cells regardless of the tissue from which they are derived. Any cell that can differentiate into cells of the mesodermal lineage, such as bone, fat, and cartilage, may be included in the scope of the present invention without limitation. In addition, the mesenchymal stem cells include all mesenchymal stem cells derived from animals, and the animals may refer to all animals, including humans, in which damaged tissue develops and can be treated through the mesenchymal stem cells of the present invention. . The animal may be not only a human, but also a mammal such as a cow, horse, sheep, pig, goat, camel, antelope, dog, or cat that requires treatment for similar symptoms, but is not limited thereto.
본 발명은 하기 [화학식 1] 내지 [화학식 4]로 표현되는 카페시타빈(Capecitabine), 노메제스트롤 아세테이트(Nomegestrol acetate), 트리메타지딘(Trimetazidine), 디클로닌 하이드로클로라이드(Dyclonine hydrochloride) 및 화합물 1 내지 화합물 18 로 이루어진 군으로부터 선택되는 1 이상을 포함하는 것을 특징으로 하는 중간엽 줄기세포 증식 또는 이동 촉진용 조성물을 제공한다.The present invention relates to capecitabine, nomegestrol acetate, trimetazidine, Dyclonine hydrochloride and compounds represented by the following [Formula 1] to [Formula 4] Provided is a composition for promoting proliferation or migration of mesenchymal stem cells, comprising at least one selected from the group consisting of compounds 1 to 18.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
상기 카페시타빈(Capecitabine)은 유방암, 위암 및 대장암의 치료제로, 노메제스트롤 아세테이트(Nomegestrol acetate)은 피임약, 폐경 호르몬 요법에 사용되는 프로게스틴계 약물로, 트리메타지딘(Trimetazidine)은 세포 보호 항 허혈 치료제로, 디클로닌 하이드로클로라이드(Dyclonine hydrochloride)는 구강 등의 국소 마취제로 각각 FDA 승인된 화합물이다.Capecitabine is a treatment for breast cancer, stomach cancer, and colon cancer, Nomegestrol acetate is a progestin-based drug used in contraceptive pills and menopausal hormone therapy, and Trimetazidine is a cell protective agent. As a treatment for ischemia, Dyclonine hydrochloride is a compound approved by the FDA as a local anesthetic for oral use.
이때 상기 중간엽 줄기세포는 제대, 제대혈, 골수, 지방, 근육, 신경, 피부, 양막 및 태반으로 구성된 군에서 선택되는 1종 이상의 조직으로부터 유래된 중간엽 줄기세포일 수 있다.At this time, the mesenchymal stem cells may be mesenchymal stem cells derived from one or more types of tissues selected from the group consisting of umbilical cord, cord blood, bone marrow, fat, muscle, nerve, skin, amniotic membrane, and placenta.
본 발명은 상기 [화학식 1] 내지 [화학식 4]로 표현되는 카페시타빈(Capecitabine), 노메제스트롤 아세테이트(Nomegestrol acetate), 트리메타지딘(Trimetazidine), 디클로닌 하이드로클로라이드(Dyclonine hydrochloride) 및 화합물 1 내지 화합물 18 로 이루어진 군으로부터 선택되는 1 이상을 포함하는 것을 특징으로 하는 중간엽 줄기세포 증식 및 이동 촉진용 조성물을 제공한다.The present invention relates to capecitabine, nomegestrol acetate, trimetazidine, Dyclonine hydrochloride and compounds represented by [Formula 1] to [Formula 4]. Provided is a composition for promoting proliferation and migration of mesenchymal stem cells, comprising at least one selected from the group consisting of compounds 1 to 18.
이때 상기 중간엽 줄기세포는 제대, 제대혈, 골수, 지방, 근육, 신경, 피부, 양막 및 태반으로 구성된 군에서 선택되는 1종 이상의 조직으로부터 유래된 중간엽 줄기세포일 수 있다.At this time, the mesenchymal stem cells may be mesenchymal stem cells derived from one or more types of tissues selected from the group consisting of umbilical cord, cord blood, bone marrow, fat, muscle, nerve, skin, amniotic membrane, and placenta.
상기 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물은 약학 조성물로 제조될 수 있다. 상기 중간엽 줄기세포 증식 및 이동 촉진용 조성물을 포함하는 약학 조성물은 사람 및 동물의 손상 조직에서 골, 지방 및 연골 등으로 분화함으로써 손상 조직의 치료에 직접적으로 기여할 수 있다.The composition for promoting mesenchymal stem cell proliferation and/or migration may be prepared as a pharmaceutical composition. The pharmaceutical composition containing the composition for promoting mesenchymal stem cell proliferation and migration can directly contribute to the treatment of damaged tissues in humans and animals by differentiating them into bone, fat, and cartilage.
상기 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물은 전체 약학 조성물 총 중량에 대하여 바람직하게는 0.001~50중량%, 더 바람직하게는 0.001~40중량%, 가장 바람직하게는 0.001~30중량%로 하여 첨가될 수 있다.The composition for promoting mesenchymal stem cell proliferation and/or migration is preferably 0.001 to 50% by weight, more preferably 0.001 to 40% by weight, and most preferably 0.001 to 30% by weight, based on the total weight of the entire pharmaceutical composition. It can be added.
본 발명의 약제학적 조성물은 비경구 투여할 수 있으며, 예를 들어 손상조직 내에 직접 주사 방식으로 투여할 수 있다. 본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약제학적 조성물의 일반적인 투여량은 성인 기준으로 1일 당 102~1010 세포이다.The pharmaceutical composition of the present invention can be administered parenterally, for example, by direct injection into damaged tissue. The appropriate dosage of the pharmaceutical composition of the present invention is prescribed in various ways depending on factors such as formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity. It can be. The general dosage of the pharmaceutical composition of the present invention is 10 2 to 10 10 cells per day for adults.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제 또는 유화액 형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.상기 약학적 조성물은, 약제학적으로 허용되는 담체를 포함한다. 본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.The pharmaceutical composition of the present invention is prepared in unit dosage form by formulating it using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily performed by a person skilled in the art. Alternatively, it can be manufactured by placing it in a multi-capacity container. At this time, the formulation may be in the form of a solution, suspension, syrup or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, powder, granule, tablet or capsule, and may additionally contain a dispersant or stabilizer. The composition includes a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in preparation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, Includes, but is limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. It doesn't work. In addition to the above ingredients, the pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween)-61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween-61, cacao, laurin, glycerogeratin, etc. can be used.
본 발명의 약학적 조성물은 쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 주사 및 피부 도포에 의해 투여될 수 있다.The pharmaceutical composition of the present invention can be administered to mammals such as rats, livestock, and humans through various routes. All modes of administration are contemplated, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection and dermal application.
본 발명의 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물은 중간엽 줄기세포의 전처리(preconditioning)에 사용될 수 있다. 본 발명의 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물을 중간엽 줄기세포의 전처리(preconditioning)에 사용하는 경우, 중간엽 줄기세포의 생존률을 증가시키고, 중간엽 줄기세포의 이동 및/또는 증식에 도움이 될 수 있으며, 중간엽 줄기세포의 조직 내 주입 시, 중간엽 줄기세포의 생존률, 이동 및/또는 증식을 촉진시켜 치료효과를 증가시킬 수 있다.The composition for promoting mesenchymal stem cell proliferation and/or migration of the present invention can be used for preconditioning of mesenchymal stem cells. When the composition for promoting mesenchymal stem cell proliferation and/or migration of the present invention is used for preconditioning mesenchymal stem cells, the survival rate of mesenchymal stem cells is increased, and the migration and/or proliferation of mesenchymal stem cells is increased. When injecting mesenchymal stem cells into a tissue, it can increase the therapeutic effect by promoting the survival rate, migration, and/or proliferation of mesenchymal stem cells.
본 발명은 중간엽 줄기세포의 배양 전, 배양 중, 또는 배양 후에 중간엽 줄기세포를 상기 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물로 처리한 중간엽 줄기세포를 제공한다.The present invention provides mesenchymal stem cells treated with the composition for promoting mesenchymal stem cell proliferation and/or migration before, during, or after culturing the mesenchymal stem cells.
또한, 본 발명은 중간엽 줄기세포의 배양 전, 배양 중, 또는 배양 후에 중간엽 줄기세포를 상기 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물로 처리한 중간엽 줄기세포를 배양한 조절 배양액(conditioned medium)을 제공한다.In addition, the present invention provides a conditioned culture medium ( conditioned medium) is provided.
본 발명은 중간엽 줄기세포의 배양 전 중간엽 줄기세포를 상기 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물로 전처리한 조절 배양액(conditioned medium)으로부터 분리, 정제된 세포외입자(extracellular vehicles), 유전자 및 단백질을 포함하는 것을 특징으로 하는 치료 조성물을 제공한다.The present invention provides extracellular particles (extracellular vehicles) separated and purified from a conditioned medium in which mesenchymal stem cells are pretreated with a composition for promoting mesenchymal stem cell proliferation and/or migration before culturing mesenchymal stem cells; A therapeutic composition comprising genes and proteins is provided.
상기 치료 조성물은 치료목적에 따라, 연골세포 (chondrocyte), 골아세포(osteoblast), 지방세포(adipocyte), 근육세포(myocyte), 신경세포(neuron) 및 심근세포로 분화 유도할 수 있으며, 연골, 골조직종양 제거 수술, 화상 등에 의해 생긴 연부조직결손을 치료할 생체 재료 생산에 이용될 수 있다.Depending on the purpose of treatment, the therapeutic composition can induce differentiation into chondrocytes, osteoblasts, adipocytes, myocytes, neurons, and cardiomyocytes, cartilage, It can be used to produce biomaterials to treat soft tissue defects caused by bone tissue tumor removal surgery, burns, etc.
본 발명은 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물에 관한 것으로, 중간엽 줄기세포의 이식을 통한 치료 효율을 증대시킬 수 있을 것으로 기대된다.The present invention relates to a composition for promoting mesenchymal stem cell proliferation and/or migration, and is expected to increase treatment efficiency through transplantation of mesenchymal stem cells.
도 1은 중간엽 줄기세포(MSC)의 이동(igration)에 대한 capecitabine, Trimetazidine 및 Nomegestrol acetate의 효과를 나타내는 사진이다.
도 2는 Dyclonine hydrochloride의 농도에 따른 중간엽 줄기세포(MSC) hBM MSC 2 (A) 및 hBM MSC 3 (B)의 증식(proliferation)에 대한 효과를 나타낸 그래프이다.
도 3은 중간엽 줄기세포(MSC)의 이동(igration)에 대한 화합물 7, 화합물 13 및 화합물 17의 효과를 나타내는 사진이다.Figure 1 is a photograph showing the effects of capecitabine, Trimetazidine, and Nomegestrol acetate on the migration of mesenchymal stem cells (MSC).
Figure 2 is a graph showing the effect on proliferation of mesenchymal stem cells (MSC) hBM MSC 2 (A) and hBM MSC 3 (B) depending on the concentration of Dyclonine hydrochloride.
Figure 3 is a photograph showing the effect of Compound 7, Compound 13, and Compound 17 on the migration of mesenchymal stem cells (MSC).
이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해지고, 당업자에게 본 발명의 사상을 충분히 전달하기 위해 제공하는 것이다.Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the content introduced herein is provided to be thorough and complete, and to fully convey the spirit of the present invention to those skilled in the art.
<< 실시예Example 1. One. 중간엽mesenchyme 줄기세포 증식 및/또는 이동 촉진 화합물 확인> Identification of compounds that promote stem cell proliferation and/or migration>
본 발명자들은 중간엽 줄기세포 증식 및/또는 이동을 촉진하는 화합물을 다음과 같이 스크리닝하였다.The present inventors screened compounds that promote mesenchymal stem cell proliferation and/or migration as follows.
실시예Example 1.1 1.1 카페시타빈Capecitabine , , 노메제스트롤nomegestrol 아세테이트, acetate, 트리메타지딘trimetazidine , , 디클로닌dyclonine 하이드로클로라이드hydrochloride
본 발명의 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물은 하기 [화학식 1]로 표현되는 카페시타빈(Capecitabine), 노메제스트롤 아세테이트(Nomegestrol acetate), 트리메타지딘(Trimetazidine) 및 디클로닌 하이드로클로라이드(Dyclonine hydrochloride) 으로 구성된 군으로부터 선택되는 1을 포함한다.The composition for promoting mesenchymal stem cell proliferation and/or migration of the present invention includes Capecitabine, Nomegestrol acetate, Trimetazidine, and Dyclonine, represented by the following [Chemical Formula 1] It includes 1 selected from the group consisting of hydrochloride (Dyclonine hydrochloride).
[화학식 1][Formula 1]
실시예Example 1.2 화합물 1 내지 화합물 11 1.2 Compound 1 to Compound 11
본 발명의 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물은 하기 [화학식 2]로 표현되는 화합물 1 내지 11로 구성된 군으로부터 선택되는 1을 포함한다.The composition for promoting mesenchymal stem cell proliferation and/or migration of the present invention includes 1 selected from the group consisting of compounds 1 to 11 represented by the following [Formula 2].
[화학식 2][Formula 2]
상기 화합물 1 내지 11의 화학명 및 smiles 는 표 1에 나타내었다.The chemical names and smiles of compounds 1 to 11 are shown in Table 1.
실시예Example 1.3 화합물 12 및 화합물 13 1.3 Compound 12 and Compound 13
본 발명의 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물은 또한 하기 [화학식 3]으로 표현되는 화합물 12 및 화합물 13으로 구성된 군으로부터 선택되는 1을 포함한다.The composition for promoting mesenchymal stem cell proliferation and/or migration of the present invention also includes 1 selected from the group consisting of Compound 12 and Compound 13 represented by the following [Formula 3].
[화학식 3][Formula 3]
상기 화합물 12 또는 13의 화학명 및 smiles 는 표 2에 나타내었다.The chemical names and smiles of compounds 12 or 13 are shown in Table 2.
실시예Example 1.4 화합물 14 내지 화합물 18 1.4 Compounds 14 to 18
본 발명의 중간엽 줄기세포 증식 및/또는 이동 촉진용 조성물은 하기 [화학식 4]로 표현되는 화합물 14 내지 화합물 18으로 구성된 군으로부터 선택되는 1 을 포함한다.The composition for promoting mesenchymal stem cell proliferation and/or migration of the present invention includes 1 selected from the group consisting of compounds 14 to 18 represented by the following [Formula 4].
[화학식 4][Formula 4]
상기 화합물 14 내지 18의 화학명 및 smiles 는 표 3에 나타내었다.The chemical names and smiles of compounds 14 to 18 are shown in Table 3.
<< 실시예Example 2. 인간 유래 2. Human origin 중간엽줄기세포의of mesenchymal stem cells 배양> Culture>
인간 유래 중간엽줄기세포 (human mesenchymal stem cell, 이하 hMSC 이라 명명함)는 인간의 경골 (tibiae) 및 대퇴골 (femurs)의 골수 (Bone marrow) 세포에서 수득하여, 각각의 세포를 hBM-MSC-2와 hBM-MSC-3으로 명기하여 사용하였다. hMSC는 CSBM-A06 배지 (코아스템(주), Korea)에 10% 소태아혈청 (FBS, fetal bovine serum; HyClone, Logan, UT, USA, #SH30919.03) 및 1% 페니실린 스트렙토마이신 (Penicillin streptomycin; HyClone, Logan, UT, USA, #SV30010)과 2.5mM GlutaMAX™ supplement (Thermo Scientific, IL, USA, #35050061) 이 포함된 배지에서 37℃, 7% CO2 조건에서 배양하였다.Human mesenchymal stem cells (hereinafter referred to as hMSC) are obtained from bone marrow cells of human tibiae and femurs, and each cell is called hBM-MSC-2. and hBM-MSC-3. hMSCs were grown in CSBM-A06 medium (Corestem Co., Ltd., Korea) supplemented with 10% fetal bovine serum (FBS; HyClone, Logan, UT, USA, #SH30919.03) and 1% penicillin streptomycin. ; HyClone, Logan, UT, USA, #SV30010) and 2.5mM GlutaMAX™ supplement (Thermo Scientific, IL, USA, #35050061) were cultured at 37°C and 7% CO 2 conditions.
<< 실시예Example 3. 3. 카페시타빈Capecitabine , , 노메제스트롤nomegestrol 아세테이트 및 acetate and 트리메타지딘trimetazidine 의 of 중간엽mesenchyme 줄기세포 Stem Cells 생존률에survival rate 미치는 효과 확인> Check the effects>
상기 [화학식 1]의 카페시타빈, 노메제스트롤 아세테이트 및 트리메타지딘 의 세포 생존능을 확인하였다. 인간 유래 중간엽줄기세포의 세포 생존능력은 CCK-8 (Cell Counting Kit-8) 시약 (LPS solution, Seoul, Korea, #CYT3000)을 이용해 측정하였다. 스크리닝은 hBM-MSC-3 세포를 사용하였다. 세포는 96웰 플레이트 (Corning, NY, USA, #353072)에 웰 당 2 × 103 개의 세포를 분주하여, 37℃ 및 7% CO2 조건에서 24시간 배양 후 물질을 처리하였다. 카페시타빈, 노메제스트롤 아세테이트 및 트리메타지딘 10 μM 을 72시간 동안 처리 한 후 각각의 well에 10 μl CCK-8을 첨가하여 충분히 색이 변할 정도로 배양하였다. 색이 변한 배지는 Hidex sense microplate reader (Hidex, Turku, Finland, #425-301)를 이용해 450 nm 파장의 흡광도를 측정하여 정량화하였다. 실험값은 대조군을 100%로 뒀을 때 상대적인 %값을 사용하였으며, 세 번의 독립적인 실험을 통해 확인하고 결과를 표 4에 나타내었다. 하기 표 4에서 보는 바와 같이, 카페시타빈, 노메제스트롤 아세테이트 및 트리메타지딘은 세포 독성을 나타내지 않았다.The cell viability of capecitabine, nomegestrol acetate, and trimetazidine of [Formula 1] was confirmed. Cell viability of human-derived mesenchymal stem cells was measured using CCK-8 (Cell Counting Kit-8) reagent (LPS solution, Seoul, Korea, #CYT3000). For screening, hBM-MSC-3 cells were used. Cells were distributed at 2 × 10 3 cells per well in a 96-well plate (Corning, NY, USA, #353072), and cultured at 37°C and 7% CO 2 for 24 hours before processing. After treatment with 10 μM of capecitabine, nomegestrol acetate, and trimetazidine for 72 hours, 10 μl CCK-8 was added to each well and cultured until the color changed sufficiently. The color-changing medium was quantified by measuring the absorbance at a wavelength of 450 nm using a Hidex sense microplate reader (Hidex, Turku, Finland, #425-301). The experimental values used were relative percentage values when the control group was set at 100%, and were confirmed through three independent experiments, and the results are shown in Table 4. As shown in Table 4 below, capecitabine, nomegestrol acetate, and trimetazidine did not show cytotoxicity.
<< 실시예Example 4. 4. 카페시타빈Capecitabine , , 노메제스트롤nomegestrol 아세테이트 및 acetate and 트리메타지딘trimetazidine 의 of 중간엽mesenchyme 줄기세포 이동 능력에 미치는 효과 확인> Check the effect on stem cell migration ability>
세포 이동능력은 hBM-MSC-3세포를 활용하여, boyden 챔버 (chamber)와 transwell 챔버를 이용해 평가하였다.Cell migration ability was evaluated using hBM-MSC-3 cells, Boyden chamber and transwell chamber.
Boyden 챔버 방법은 8μm pores polycarbonate membrane (neuro probe, MD, USA, #PFB8)을 0.2% 젤라틴 (merck, MO, USA, #G2625)으로 코팅한 후 건조 시켜 사용하였다. Bottom chamber에 각 웰에 10% 소태아혈청이 포함된 배지를 33 ㎕씩 넣어준 후 멤브레인을 올리고 tap 챔버를 올려 나사로 고정시킨다. Top 챔버의 각 웰에 50 ㎕의 0.1% 소태아혈청이 포함된 배지에 5 × 103개의 세포가 포함되게 넣어준 후 24시간 동안 7% CO2, 37℃ 조건에서 배양한다. 배양이 완료되면 멤브레인을 분리하여 Diff Quik (sysmex, kobe, Japan, #38721) 시약을 이용해 염색한 후 현미경으로 각 군의 세포 수를 세었다. 그리고, 대조군 세포 수를 100%로 두었을 때 상대적인 값을 %로 표기하여 사용하였으며, student t-test 방법으로 통계 처리를 하여, p<0.05 이하일 때 통계적인 유의성을 가짐을 표기하였다.The Boyden chamber method was used by coating an 8μm pores polycarbonate membrane (neuro probe, MD, USA, #PFB8) with 0.2% gelatin (merck, MO, USA, #G2625) and then drying it. After adding 33 ㎕ of medium containing 10% fetal bovine serum to each well in the bottom chamber, raise the membrane and secure it with a screw. In each well of the top chamber, 5 × 10 3 cells were added to 50 ㎕ of medium containing 0.1% fetal bovine serum, and cultured at 7% CO 2 and 37°C for 24 hours. When culture was completed, the membrane was separated and stained using Diff Quik (sysmex, kobe, Japan, #38721) reagent, and the number of cells in each group was counted under a microscope. In addition, when the number of control cells was set at 100%, the relative value was expressed as %, and statistical processing was performed using the student t-test method, and statistical significance was indicated when p < 0.05 or less.
Transwell chamber 방법은 Nunc™ Carrier Plate for Cell Culture Insert (Thermo Scientific, IL, USA, #141006)를 사용하였다. Bottom 챔버에 각 웰에 10% 소태아혈청이 포함된 배지를 1.5 ㎖씩 넣어준 후 Top 챔버의 각 웰에 200 ㎕의 0.1% 소태아혈청이 포함된 배지에 4 × 104개의 세포가 포함되게 넣어준 후 24시간 동안 7% CO2, 37℃ 조건에서 배양한다. 배양이 완료되면 top chamber를 Diff Quik 시약을 이용해 염색하여 현미경으로 세포를 관찰하고, 이를 도 1에 나타내었다.The Transwell chamber method used Nunc™ Carrier Plate for Cell Culture Insert (Thermo Scientific, IL, USA, #141006). After adding 1.5 ㎖ of medium containing 10% fetal bovine serum to each well of the bottom chamber, 4 × 10 4 cells were added to 200 ㎕ of medium containing 0.1% fetal bovine serum in each well of the top chamber. After addition, culture is carried out under conditions of 7% CO 2 and 37°C for 24 hours. When culture was completed, the top chamber was stained using Diff Quik reagent and the cells were observed under a microscope, which is shown in Figure 1.
도 1에서 보는 바와 같이, 카페시타빈, 노메제스트롤 아세테이트 및 트리메타지딘을 처리한 군이 대조군에 비해 더 많은 세포가 이동하여 이동촉진 능력을 나타내는 것을 확인할 수 있었다.As shown in Figure 1, it was confirmed that more cells in the group treated with capecitabine, nomegestrol acetate, and trimetazidine moved compared to the control group, showing the ability to promote migration.
<< 실시예Example 5. 5. 디클로닌dyclonine 하이드로클로라이드의of hydrochloride 중간엽mesenchyme 줄기세포 증식에 미치는 효과 확인> Check the effect on stem cell proliferation>
hBM-MSC-2 및 hBM-MSC-3을 96웰 플레이트 (Corning, NY, USA, #353072)에 웰 당 2 × 103 개의 세포를 분주하여, 37℃ 및 7% CO2 조건에서 24시간 배양 후 디클로닌 하이드로클로라이드를 1, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 μM이 되도록 각각 처리하였다. 72시간 동안 처리 한 후 각각의 well에 10 μl CCK-8을 첨가하여 충분히 색이 변할 정도로 배양하였다. 색이 변한 배지는 Hidex sense microplate reader (Hidex, Turku, Finland, #425-301)를 이용해 450 nm 파장의 흡광도를 측정하여 정량화하였다. 실험값은 대조군을 100%로 뒀을 때 상대적인 %값을 사용하였으며, 세 번의 독립적인 실험을 통해 확인하고 이를 표 5 및 도 2에 나타내었다.hBM-MSC-2 and hBM-MSC-3 were distributed at 2 × 10 3 cells per well in a 96-well plate (Corning, NY, USA, #353072) and cultured for 24 hours at 37°C and 7% CO 2 conditions. Afterwards, dyclonine hydrochloride was treated to concentrations of 1, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, and 30 μM, respectively. After treatment for 72 hours, 10 μl CCK-8 was added to each well and cultured until the color changed sufficiently. The color-changing medium was quantified by measuring the absorbance at a wavelength of 450 nm using a Hidex sense microplate reader (Hidex, Turku, Finland, #425-301). The experimental values used were relative percentage values when the control group was set at 100%, and were confirmed through three independent experiments and are shown in Table 5 and Figure 2.
증식률 (% of control)hBM-MSC-2
Proliferation rate (% of control)
증식률 (% of control)hBM-MSC-3
Proliferation rate (% of control)
표 5 및 도 2에서 보는 바와 같이 디클로닌 하이드로클로라이드는 농도 의존적으로 중간엽 줄기세포의 증식을 촉진하였다.As shown in Table 5 and Figure 2, dyclonine hydrochloride promoted the proliferation of mesenchymal stem cells in a concentration-dependent manner.
<< 실시예Example 6. 화합물 1 내지 18의 6. Compounds 1 to 18 중간엽mesenchyme 줄기세포 증식에 미치는 효과 확인> Check the effect on stem cell proliferation>
상기 실시예 5와 동일한 방법으로 화합물 1 내지 18의 세포가 중간엽 줄기세포 증식에 미치는 효과를 확인하고 그 결과를 표 6에 나타내었다. 단 각 화합물은 최종농도 10 μM이 되도록 하여 72시간 동안 처리하고, 각각의 well에 10 μl CCK-8을 첨가하여 충분히 색이 변할 정도로 배양하였다. 색이 변한 배지는 Hidex sense microplate reader (Hidex, Turku, Finland, #425-301)를 이용해 450 nm 파장의 흡광도를 측정하여 정량화하였다. 실험값은 대조군을 100%로 뒀을 때 상대적인 %값을 사용하였으며, 세 번의 독립적인 실험을 통해 확인하고 이를 표 6에 나타내었다.The effect of compounds 1 to 18 on mesenchymal stem cell proliferation was confirmed in the same manner as in Example 5, and the results are shown in Table 6. However, each compound was treated for 72 hours at a final concentration of 10 μM, and 10 μl CCK-8 was added to each well and cultured until the color changed sufficiently. The color-changed medium was quantified by measuring the absorbance at a wavelength of 450 nm using a Hidex sense microplate reader (Hidex, Turku, Finland, #425-301). The experimental values used were relative percentage values when the control group was set at 100%, and were confirmed through three independent experiments and are shown in Table 6.
증식률 (% of control)hBM-MSC-2
Proliferation rate (% of control)
증식률 (% of control)hBM-MSC-3
Proliferation rate (% of control)
상기 표 6에서 보는 바와 같이, 화합물 1 내지 18은 모두 각 처리 농도에서 세포독성을 나타내지 않았으며, 일정한 중간엽 줄기세포의 증식 촉진 효과를 나타내었다. 특히, 화합물 2, 4, 5, 6, 9, 13~16은 hBM-MSC-2 줄기세포에서, 화합물 1, 5~7, 9~12, 14~18은 hBM-MSC-3 줄기세포에서 대조군보다 20% 이상의 증식 촉진 효과를 나타내었다.As shown in Table 6, compounds 1 to 18 did not exhibit cytotoxicity at each treatment concentration and showed a certain proliferation-promoting effect on mesenchymal stem cells. In particular, compounds 2, 4, 5, 6, 9, 13-16 were used in hBM-MSC-2 stem cells, and compounds 1, 5-7, 9-12, and 14-18 were used in hBM-MSC-3 stem cells as a control group. It showed a proliferation promoting effect of more than 20%.
<< 실시예Example 7. 7. 중간엽mesenchyme 줄기세포 ( Stem Cells ( MSCM.S.C. )의 이동(migration)과 증식(proliferation)을 동시에 촉진하는 화합물 확인 >) Identification of compounds that simultaneously promote migration and proliferation >
상기 카페시타빈, 노메제스트롤 아세테이트, 트리메타지딘, 디클로닌 하이드로클로라이드 및 화합물 1 내지 18 중 중간엽 줄기세포 (MSC)의 이동(migration)과 증식(proliferation)을 동시에 촉진하는 화합물을 확인하였다.Among the capecitabine, nomegestrol acetate, trimetazidine, dyclonine hydrochloride, and compounds 1 to 18, compounds that simultaneously promote migration and proliferation of mesenchymal stem cells (MSC) were identified. .
상기 실시예 4와 동일한 방법으로, 세포 이동능력은 hBM-MSC-3세포를 활용하여, boyden 챔버 (chamber)와 transwell 챔버를 이용해 평가하였으며, 상기 화합물 중, 화합물 1~3 의 줄기세포 (MSC)의 이동(migration)에 대한 효과를 도 3에 나타내었다.In the same manner as Example 4, cell migration ability was evaluated using hBM-MSC-3 cells, a boyden chamber and a transwell chamber. Among the compounds, stem cells (MSC) of compounds 1 to 3 The effect on migration is shown in Figure 3.
도 3에서 보는 바와 같이, 화합물 7, 화합물 13 및 화합물 17 은 줄기세포 (MSC)의 이동(migration)을 촉진시켰으며, 상기 표 6에서 보는 바와 같이, 줄기세포의 증식 또한 촉진시키는 것을 확인하였다.As shown in Figure 3, Compound 7, Compound 13, and Compound 17 promoted the migration of stem cells (MSCs), and as shown in Table 6 above, it was confirmed that they also promoted the proliferation of stem cells.
Claims (4)
[화학식]
A composition for promoting proliferation or migration of mesenchymal stem cells, comprising at least one selected from the group consisting of compounds 1, 2, and 3 represented by the following [chemical formula].
[Chemical formula]
상기 중간엽 줄기세포는 제대, 제대혈, 골수, 지방, 근육, 신경, 피부, 양막 및 태반으로 구성된 군에서 선택되는 1종 이상의 조직으로부터 유래된 중간엽 줄기세포인 것을 특징으로 하는 중간엽 줄기세포 증식 또는 이동 촉진용 조성물.According to paragraph 1,
Mesenchymal stem cell proliferation, characterized in that the mesenchymal stem cells are mesenchymal stem cells derived from one or more tissues selected from the group consisting of umbilical cord, cord blood, bone marrow, fat, muscle, nerve, skin, amniotic membrane, and placenta. or a composition for promoting movement.
[화학식]
A composition for promoting proliferation and migration of mesenchymal stem cells, comprising at least one selected from the group consisting of compounds 1, 2, and 3 represented by the following [chemical formula].
[Chemical formula]
상기 중간엽 줄기세포는 제대, 제대혈, 골수, 지방, 근육, 신경, 피부, 양막 및 태반으로 구성된 군에서 선택되는 1종 이상의 조직으로부터 유래된 중간엽 줄기세포인 것을 특징으로 하는 중간엽 줄기세포 증식 및 이동 촉진용 조성물.According to paragraph 3,
Mesenchymal stem cell proliferation, characterized in that the mesenchymal stem cells are mesenchymal stem cells derived from one or more tissues selected from the group consisting of umbilical cord, cord blood, bone marrow, fat, muscle, nerve, skin, amniotic membrane, and placenta. and compositions for promoting movement.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020230161226A KR20230161925A (en) | 2021-02-19 | 2023-11-20 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020210022460A KR102647353B1 (en) | 2021-02-19 | 2021-02-19 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
| KR1020230161226A KR20230161925A (en) | 2021-02-19 | 2023-11-20 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020210022460A Division KR102647353B1 (en) | 2021-02-19 | 2021-02-19 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20230161925A true KR20230161925A (en) | 2023-11-28 |
Family
ID=83113112
Family Applications (6)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020210022460A KR102647353B1 (en) | 2021-02-19 | 2021-02-19 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
| KR1020230109078A KR20230125766A (en) | 2021-02-19 | 2023-08-21 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
| KR1020230109113A KR20230126693A (en) | 2021-02-19 | 2023-08-21 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
| KR1020230161208A KR102613653B1 (en) | 2021-02-19 | 2023-11-20 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
| KR1020230161187A KR20230163974A (en) | 2021-02-19 | 2023-11-20 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
| KR1020230161226A KR20230161925A (en) | 2021-02-19 | 2023-11-20 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
Family Applications Before (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020210022460A KR102647353B1 (en) | 2021-02-19 | 2021-02-19 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
| KR1020230109078A KR20230125766A (en) | 2021-02-19 | 2023-08-21 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
| KR1020230109113A KR20230126693A (en) | 2021-02-19 | 2023-08-21 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
| KR1020230161208A KR102613653B1 (en) | 2021-02-19 | 2023-11-20 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
| KR1020230161187A KR20230163974A (en) | 2021-02-19 | 2023-11-20 | Composition for inducing proliferation and/or migration of mesenchymal stem cells |
Country Status (1)
| Country | Link |
|---|---|
| KR (6) | KR102647353B1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116083355B (en) * | 2023-03-09 | 2023-12-01 | 广东赛尔生物科技有限公司 | Method for improving therapeutic capacity of umbilical mesenchymal stem cells |
| CN117625528B (en) * | 2024-01-26 | 2024-04-12 | 苏州科为康生物医药科技有限公司 | Preparation method of mesenchymal stem cells |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20100063696A (en) | 2007-07-05 | 2010-06-11 | 리제너러티브 사이언시즈, 엘엘씨 | Methods and compositions for optimized expansion and implantation of mesenchymal stem cells |
| KR101229819B1 (en) | 2009-10-19 | 2013-02-08 | 코아스템(주) | Compositions for Improving Migration Potential of Stem Cells |
| KR20130085863A (en) | 2012-01-20 | 2013-07-30 | 인하대학교 산학협력단 | Composition for inducing migration of mesenchymal stem cells |
| KR101466811B1 (en) | 2011-03-08 | 2014-11-28 | 테고사이언스 (주) | In vivo Induction Methods for Migrating Stem Cells to a Target Site |
| KR102025474B1 (en) | 2017-10-30 | 2019-09-25 | 사회복지법인 삼성생명공익재단 | Methods for improving migration of stem cell using ethionamide |
-
2021
- 2021-02-19 KR KR1020210022460A patent/KR102647353B1/en active IP Right Grant
-
2023
- 2023-08-21 KR KR1020230109078A patent/KR20230125766A/en not_active Application Discontinuation
- 2023-08-21 KR KR1020230109113A patent/KR20230126693A/en not_active Application Discontinuation
- 2023-11-20 KR KR1020230161208A patent/KR102613653B1/en active IP Right Grant
- 2023-11-20 KR KR1020230161187A patent/KR20230163974A/en not_active Application Discontinuation
- 2023-11-20 KR KR1020230161226A patent/KR20230161925A/en not_active Application Discontinuation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20100063696A (en) | 2007-07-05 | 2010-06-11 | 리제너러티브 사이언시즈, 엘엘씨 | Methods and compositions for optimized expansion and implantation of mesenchymal stem cells |
| KR101229819B1 (en) | 2009-10-19 | 2013-02-08 | 코아스템(주) | Compositions for Improving Migration Potential of Stem Cells |
| KR101466811B1 (en) | 2011-03-08 | 2014-11-28 | 테고사이언스 (주) | In vivo Induction Methods for Migrating Stem Cells to a Target Site |
| KR20130085863A (en) | 2012-01-20 | 2013-07-30 | 인하대학교 산학협력단 | Composition for inducing migration of mesenchymal stem cells |
| KR102025474B1 (en) | 2017-10-30 | 2019-09-25 | 사회복지법인 삼성생명공익재단 | Methods for improving migration of stem cell using ethionamide |
Non-Patent Citations (4)
| Title |
|---|
| James A Ankrum, Joon Faii Ong 2, Jeffrey M Karp, Mesenchymal stem cells: immune evasive, not immune privileged, Nat Biotechnol. 2014, Mar;32(3):252-60. |
| Mark F. Pittenger et al., Multilineage Potential of Adult Human Mesenchymal Stem Cells, 1999, Science 284, 143 |
| R. J. Deans, A. B. Moseley, Mesenchymal stem cells: biology and potential clinical uses, 2000, Exp Hematol. Aug;28(8):875-84. |
| W. J. C. Rombouts, R E Ploemacher, Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture, Leukemia. 2003 Jan;17(1):160-70. |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20220118709A (en) | 2022-08-26 |
| KR20230126692A (en) | 2023-08-30 |
| KR20230161407A (en) | 2023-11-27 |
| KR20230163974A (en) | 2023-12-01 |
| KR20230126693A (en) | 2023-08-30 |
| KR20230125766A (en) | 2023-08-29 |
| KR102613653B1 (en) | 2023-12-13 |
| KR102647353B1 (en) | 2024-03-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102613653B1 (en) | Composition for inducing proliferation and/or migration of mesenchymal stem cells | |
| CN1127343C (en) | Myoblast therapy for mammalian diseases | |
| Chen et al. | Transplantation of bone marrow stromal cells for peripheral nerve repair | |
| ES2432744T3 (en) | Extramedullary adipose tissue cells and their applications in cardiac tissue reconstitution | |
| US9688733B2 (en) | Method for treating spinal cord injury using HMGB1 fragment | |
| CN110461344A (en) | For treating the composition of newborn HIE | |
| KR20180035700A (en) | Pharmaceutical composition for treating drug resistance cancer comprising exosomes extracted from stem cells which differentiate | |
| WO2020013090A1 (en) | Production method for neuron-like cells | |
| KR100791487B1 (en) | A method for isolating and culturing mesenchymal stem cell derived from umbilical cord blood | |
| WO2024049158A1 (en) | Isolation and culture conditions of peripheral blood-derived stem cells, and induction of differentiation into progenitor cells by using same | |
| KR101389851B1 (en) | Method for Culture of Neural Crest Stem Cells and Uses Therefor | |
| KR102664092B1 (en) | Composition for inducing proliferation and/or migration of mesenchymal stem cells | |
| WO2017131353A1 (en) | Method for inducing transdifferentiation of fibroblasts into chondrocytes | |
| US20210095247A1 (en) | Method for differentiating motor neurons from tonsil-derived mesenchymal stem cells | |
| WO2019190175A2 (en) | Method for differentiating motor neurons from tonsil-derived mesenchymal stem cells | |
| WO2019221477A1 (en) | Composition for promoting stem cell differentiation, comprising progenitor cell culture solution and multilayer graphene film, and use thereof | |
| WO2012115298A1 (en) | Agent for treating urinary incontinence including stem cells derived from amniotic fluid | |
| KR101914580B1 (en) | Composition for preventing, improving or treating cranial nerve or spinal nerve related disease comprising conditioned medium powder from stem cells | |
| KR102637401B1 (en) | Lenograstim leading to induce stem cells into motor neuron progenitor cells and differentiate into motor neuron | |
| KR101673318B1 (en) | Cell therapy composition for healing wounds comprising mesenchymal stem cell or the culture medium treated with silver nano particle | |
| KR101539822B1 (en) | Method for preparing concentrated cell culture medium via 3D-culture and use thereof | |
| US20220313741A1 (en) | Pluripotent stem cells inducing osteochondral repair | |
| KR20230013415A (en) | Composition for inducing migration of mesenchymal stem cells | |
| Mazurkevych et al. | The effect of a fibroblast growth factor, insulin-like growth factor, growth hormone, and Biolaminin 521 LN on the proliferative activity of cat stem cells | |
| WO2019088547A2 (en) | Use of ellipticine for inducing differentiation of stem cell into chondrocyte |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A107 | Divisional application of patent | ||
| E902 | Notification of reason for refusal |