CN101327223B - Medicament for treating osteonecrosis and cytoskeleton thereof - Google Patents
Medicament for treating osteonecrosis and cytoskeleton thereof Download PDFInfo
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Abstract
The invention relates to a medicine for curing osteonecrosis, belonging to the field of regenerative medicine engineering. Human amniotic mesenchymal cells (hAMCs) are used as cell source for cellular transplantation and tissue organization so as to cure the osteonecrosis and to provide a new way for repairing a damaged osseous tissue and reorganizing tissues. Based on the multi-lineage differentiation potential of the hAMCs, osteocytes, osseous tissues and vascular endotheliums can be differentiated in the human body, thereby completing the processes of osteanagenesis, bone remodeling and vascularization and forming a new osseous tissue integrated with the tissues of the patient.
Description
Technical field
The present invention relates to regenerative medicine engineering field, particularly relate to a kind of medicine for the treatment of osteonecrosis, use human amniotic membrane tissue-derived mesenchymal cells (Human amniotic mesenchymal cells, hAMCs) as the cell of Transplanted cells and tissue construction source treatment osteonecrosis, for bone tissue restoration and organization restructuring provide new way.
Background technology
1, osteonecrosis
Osteonecrosis (Osteonecrosis ON) is divided into traumatic and atraumatic two big classes, and it can involve the many joints of whole body, wherein with necrosis of femoral head (Osteonecrosis of the femoral head, ONFH) the most common and endanger the heaviest to the patient.Necrosis of femoral head is the not clear and difficult and complicated illness that is difficult to cure of the interpretation of the cause, onset and process of an illness in the present world wide, because its cause of disease complexity, the treatment difficulty in case treat untimelyly, is almost 100% high disability rate, has a strong impact on patient's life quality and work capacity.Studies show that, without effective treatment, about 80% necrotic femoral head can proceed in 1～4 year after morbidity and subside, the generation in case subside, then 87% hip joint can proceed to the joint breaking-up about 2 years, although the method for the osteoarticular treatment necrosis of femoral head of various reservations is arranged, comprise that medulla decompression, necrotic lesion are removed, marrow stromal cell is transplanted, from body bone allogenic bone transplantation, artificial bone implant, blood vessel is implanted and band blood vessel osseous tissue etc., but the final unavoidable artificial joint replacement of many patients.But the still difficult prediction of just present treatment level, young and middle-aged prosthetic replacement's long-term efficacy (＞20 years).Therefore, seek to preserve real being necessary of effective methods of treatment in patient self joint.Development along with organizational project and stem cell biological technology, the reparation that organizational project learns a skill to necrosis of femoral head provides new approach, and the research of seed cell is one of main contents wherein, utilize many differentiation potentials of stem cell and proliferation activity, the structure of expectation realization osseous tissue is reinvented, and reaches the purpose of repairing and treating osteonecrosis.
At present, the existing hospital of China utilizes mesenchymal stem cells MSCs (Bone Marrow Mesenchymal stem cells, BM-MSCs) treatment of necrosis of femoral head is carried out in transplanting, many bases also clearly illustrate that with the clinical experiment in early stage, Bone Marrow Mesenchymal Stem Cells Transplantation treatment necrosis of femoral head has very big clinical application potentiality, and the clinical trial under different condition is carried out.But adult's bone marrow MSCs (BM-MSCs) cell quantity is few, the monocyte of only discovering 0.001%～0.01% process density gradient separation produces plastic attached cell clone, and proliferation and differentiation potential descends with the increase at age, viral infection rate is higher, the collection palpus row bone marrow puncture of donor MSCs, the source is restricted, is difficult to obtain to treat the cell of desired number, restriction clinical expansion and application.
Can be used as a main source that obtains mescenchymal stem cell in view of using human childbirth " waste " amnion tissue, can evade and overcome the above problems.
2, human amniotic membrane tissue-derived mesenchymal cells
In recent years, along with people to mescenchymal stem cell (mesenchymal stem cells, MSCs) further investigation of biological characteristics and function successfully separates from people's amnion, amniotic fluid, bleeding of the umbilicus, marrow, peripheral blood, muscle, fat and fetal tissue and identifies MSCs.MSCs derives to grow an early stage mesoderm and an ectodermic class multipotential stem cell, can be differentiated to form bone, fat, cartilage, muscle even neurone, therefore in organizational project, hematopoietic stem cell transplantation and field of gene very big potential using value is arranged, become the focus of stem-cell research.
Human amniotic membrane tissue-derived mesenchymal cells (hAMCs) is a class of mesenchymal cell, Gianandrea etc. study the ultrastructure of hAMCs by using transmission electron microscope, find that hAMCs shows as the ultrastructure with epithelium and matter feature, epithelium sample feature comprises that non-enteric cavity type surface microvillus, iuntercellular connect, between the matter feature comprise: rEF profile, fat drip etc., and these characteristics have been set forth it from structure and had multinomial differentiation potential.
(1) hAMCs biological characteristics
Advanced molecular engineering such as using gene expression sequential analysis and dna microarray confirms that hAMCs expresses the characteristic antigen of stem cell.HAMCs expresses the mescenchymal stem cell marker protein: Vimentin, STRO-1 etc.; Embryonic stem cell marker protein: SSEA-3+, SSEA-4+, SSEA-1, Nanog, Oct-4; Neural stem cell marker protein: Nestin, Musashi-1 etc.; Also express stem cell correlating markings things such as SOX2, PAX6.Waveform protein positive person accounts for 97.5% in the hAMCs that cultivates, illustrate that vimentin is one of item key thing of hAMCs, can also show as Tuj 1 (+), NF-M (+), GFAP (+), cartilage genes involved (as SOX-9, SOX-5, SOX-6), bone morphogenetic protein (BMP)-2,4 and bmp receptor.
MSCs high level expression Brain Derived Neurotrophic Factor (BDNF), secretory nerve nutritional factor, neurogliocyte derived neurotrophic factor, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF) and the neurotrophic factor-3 (NT-3) in amniotic fluid source, and have the scholar that amniotic fluid MSCs and hAMCs are analyzed discovery, the two growth curve is similar, so the author thinks that the MSCs in the amniotic fluid derives from amnion probably.There is keratinocyte growth factor (KGF) mRNA to express hepatocyte neclear factor-3 β (HNF-3 β) at hAMCs.HAMCs can express the IL-1 receptor antagonist in addition, and tissue inhibitor of metalloproteinase (TIMPs)-1 ,-2 ,-3 ,-4, and IL-10 wait albumen and Fas-L.
(2) amynologic characteristic of human amnion tissue
Owing to amnion is the product that derives from fetus, be exposed to mother's immune system and monitor down, its surperficial human leucocyte antigen (HLA)--A, B, C are low to express, and expression of HLA-DR does not point out amnion transplantation not cause immunological rejection.(huaman Amnion epithelial cells, hAECs) generation of immunological rejection is not found in the experiment of storing up disease of transplantation treatment lysosome to people's amniotic epithelial cells, confirms that the amnion tissue immunogenicity is very low.Find to cultivate the chemotaxis that the amniotic epithelial cells supernatant liquor can obviously suppress neutrophilic granulocyte and scavenger cell in this external experiment in vitro, obviously reduce T, B cell proliferation by the mitotic division primary stimuli, the prompting amniotic epithelial cells may be by a kind of soluble factor inhibition of innate immune of secretion and acquired immunity.In view of CD69 is the finally expressed cell surface molecule of T cell activation, it is the triggering center of T cell activation, the expression of CD69 can be used as the secondary stimulus molecule and makes the further activation and proliferation of T cell, Hou Guanghui etc. utilize the biological nature of CD69 molecule to observe the influence of amnion tissue to human peripheral T cell activation, find that amnion tissue can not make human peripheral T cell activation and CD8+T cell subsets surface molecular CD69 express, and has confirmed the reduced immunogenicity of amnion tissue from the immunocyte biology level.HAMCs is the reduced immunogenicity cell, exception throw lymphproliferation response not, and can pass through suppressor T cell, B cell and NK cell function, influence the dendritic cell activity, can produce various somatomedins, cytokine, chemokine and proteolytic enzyme in addition and regulate immune response and change tissue microenvironment, the stimulation of endogenous stem cell alleviates the immune inflammation reaction.The low I type major histocompatibility complex (MHC-I) of expressing of hAMCs is not expressed II type major histocompatibility complex (MHC-II), can avoid immunological rejection.SUSANNE etc. compare the immunoregulatory activity of the stem cell in hAMCs, hAECs and fatty tissue source under the identical conditions, find that the performance of amnion-derived mesenchymal cell and epithelial cell immunosuppressive action depends on cells contacting and cell dosage.
(3) differentiation of hAMCs and clinical application
As a kind of multipotential cell, because the tissue difference that MSCs is settled down in vivo, various regulation and control substance differences such as the cytokine in the microenvironment, somatomedin can promote MSCs to different pedigree differentiation.During vitro culture, MSCs can be to different tissue differentiation under different inductive conditions, not only can be divided into scleroblast, adipocyte, chondrocyte and muscle cell etc., but also can stride the germinal layer differentiation, as being divided into ectodermic neurone, neurogliocyte and endoblastic liver cell etc.Gianandrea etc. study the ultrastructure of BM-MSCs, hAMCs and chorion MSCs by using transmission electron microscope, find that BM-MSCs has the chamber rough surfaced endoplasmic reticulum (rEF) that expands, the clarification vesica of assembling multi-cavity on every side, the principal character of chorion MSCs are to exist rEF to pile up, assemble a large amount of non-binding glycogens on every side; And hAMCs shows as the ultrastructure with epithelium and matter feature, and epithelium sample feature comprises that non-enteric cavity type surface microvillus, iuntercellular connect, and a matter feature comprises: rEF profile, fat drip etc., and these characteristics have been set forth it from structure and had multinomial differentiation potential.
Someone is hAMCs and newborn rat heart separate piece co-cultivation and implant the rat heart that myocardial infarction takes place, hAMCs expresses specific heart transcription factor GATA4, the specific heart gene is (as myosin light chain (MLC)-2a, MLC-2v, cTnI and CTnT), a L-type specific heart calcium channel α unit (α 1c) and the property crossed an extropism potassium-channel (Kv4.3), find simultaneously after b-FGF induces, hAMCs expresses myocardium idiosyncratic transcription factor Nkx2.5, specific heart sign atrial natriuretic peptide, expression specific heart gene α myoglobulin heavy chain after activinA induces (α-MHC), and hAECs is through b-FGF, after inducing, activinA and U-18496 do not express Nkx2.5, α-MHC and atrial natriuretic peptide illustrate that the two is distinct.HAMCs can be survived 2 months in the scar tissue of myocardial infarction at least, and can integrate and break up with cardiac muscular tissue becomes cardiac-like muscle cell.
Tomoharu finds to express coding albumin, alpha-fetoprotein by hAMCs before inducing differentiation, and (mRNA of α-FP), cytokeratin 18 (CK-18) and alpha1 Anti-trypsin (α 1-AT) does not still express the mRNA that encode G-6-Pase (G6Pase), ornithine ammonia transcarbamylase (OTC) and liver cell nuclear are transplanted 4 α (HNF-4 α); Cell said gene after inducing is expressed to be had increase in various degree and has the function that stores glycogen, and this function is one of hepatocellular specific function, and illustrating that hAMCs can break up becomes the liver cell like cell.
HAMCs can break up becomes the chondrocyte, and expression cartilage genes involved, as SOX-9, SOX-5, SOX-6, bone morphogenetic protein (BMP)-2 ,-4 and bmp receptor, after inducing the hAMCs cartilage to form, external application BMP-2 can produce 2 Collagen Type VIs and proteoglycan; HAMCs and BMP-2 are implanted in the non-cartilaginous tissue of mouse or behind the damaged place of collagen scaffold implantable bone visible hAMCs form has taken place changes and deposit with 2 Collagen Type VIs.
The MSCs that derives from matter between chorion, amnion and fine hair in addition can spontaneously be differentiated to form vascular endothelial cell external, add vascular endothelial growth factor (VEGF) and can promote this process, hAMCs express VEGF receptors-1 and 2 stimulates endothelium specificity marker FLT-1, KDR that the back expresses and ICAM increase and CD34 (+) angiogenic pseudohemophilia factor positive cell occurs through VEGF.
In sum, hAMCs has multidirectional differentiation potential.
Summary of the invention
Characteristics and the advantage in the tissue injury regenerative therapy thereof at human amniotic membrane tissue-derived mesenchymal cells (hAMCs), the invention provides a kind of medicine for the treatment of osteonecrosis, this administrated method is easy, effect obvious, the material requested source is abundant, the treatment cost is low, for the osteonecrosis treatment provides new approach.
A kind of medicine for the treatment of osteonecrosis contains human amniotic membrane tissue-derived mesenchymal cells in its effective constituent.
A kind of cytoskeleton is characterized in that being attached with said medicine on this support.
Described human amniotic membrane tissue-derived mesenchymal cells concentration is 10
6-10
6/ 1cm
3
Described cytoskeletal material is for removing the little ox bone of matrix.
Many differentiation potentials in view of hAMCs can be divided into scleroblast, osteocyte, vascular endothelial cell in vivo, finish osteanagenesis, reinvent and the vascularization process, form the freshman bone tissue of merging one with autologous tissue.Use the regenerative medicine principle, we have carried out utilizing hAMCs and taking off the research that cell calf bone compound is repaired femoral head defects, iconography and techtology have confirmed the reconstruction of femoral head defects zone osseous tissue, the fine fusion of freshman bone tissue and receptor bone, the bone trabecula edge of freshman bone tissue is attached with the active scleroblast of a large amount of propagation, have the chondrocyte in the bone trabecula, abundant vascular tissue is arranged on every side.The action effect of proof hAMCs transplantation treatment femoral head defects is obvious.
Utilize human amniotic membrane tissue-derived mesenchymal cells (hAMCs) to substitute the research of autologous bone marrow mesenchymal stem cells transplantation treatment femoral head defects, can evade and solve the weak point of mesenchymal stem cells MSCs, for the cell therapy of osteonecrosis has been opened up new cell source approach.
With respect to mesenchymal stem cells MSCs, human amniotic membrane tissue-derived mesenchymal cells also has following advantage:
1. the source is enriched, drawn materials conveniently, is easy to separate: adult's bone marrow MSCs cell quantity is few, proliferation and differentiation potential descends with the increase at age, amnion is rich in MSCs, and 8/10 second trimester and 7/10 mature amnion can be separated to hAMCs and can increase.Studies show that at about 4cm
2The amount of the former generation hAMCs that produces of amnion in 1.3-1.5 * 10
6Between individual, therefore (area approximately is 1300cm to whole amnion
2) the hAMCs number that produces can reach 4 * 10
8Individual, the somebody thinks that every gram amnion tissue produces 1,000,000 hAMCs.
2. amplification ability is better than adult bone bone marrow-drived mesenchymal stem (BM-MSCs): OCT-4 coding and relates to the associated adjustment albumen of keeping stem cell renewal and embryonic stem cell undifferentiated state, use RT-PCR and find that the OCT-4 expression is higher than BM-MSCs in hAMCs, illustrate that differentiation capability is better than BM-MSCs, by the multiplication capacity of hAMCs and BM-MSCs is relatively found, all be higher than BM-MSCs in each time point hAMCs cell counting.
3. immunogenicity is low: anti-inflammatory and reduced immunogenicity are to use the theoretical basis that amnion-derived cell carries out heteroplastic transplantation, hAMCs is the reduced immunogenicity cell, be difficult for causing the identification of antigen presenting cell (APC), thereby reduce the immunological rejection of acceptor host's immune effector cell hAMCs.HAMCs can also express anti-inflammatory and anti-angiogenic endogenous binding protein, and the interleukin 1 α (IL-1 α) and the interleukin-1 ' beta ' (IL-1 β) that obviously suppress to be caused by lipopolysaccharides raise; HAMCs also expresses Fas-L in addition, the performance immunosuppressive action.
4. pollute little: hAMCs is unique can avoiding by non-fibroblastoma cell contamination, especially can avoid being polluted by hematopoietic cell and epithelial cell, and what Cord blood, placenta and umbilical cord were originated then can not.
5. non-invasive: the collection of BM-MSCs must the row bone marrow puncture, and amnion tissue does not cause wound to donor when being the postpartum waste gathering.
6. there is not ethnics Problem.
These characteristics that hAMCs has and advantage make it at tissue injury regeneration and reconstruction, are included in the osteonecrosis treatment to have broad application prospects.
7. there is not tumorigenicity.HAMCs does not express telomerase activation, can avoid the one-tenth knurl problem of Transplanted cells.
Description of drawings
The techtology of Fig. 1 dog femoral head defects Regeneration and Repair
Wherein A is the gross anatomy sample that hAMCs-goes matrix calf bone transplantation treatment dog femoral head defects; B is that the indigo plant person of dying is the area of new bone cell; C and D: red colored part is the freshman bone tissue in the graft; E is the X line video of hAMCs transplantation treatment dog femoral head defects
The hAMCs-of vascularization removes matrix calf bone compound in the damaged model dog of Fig. 2 bone body
The interior blood vessel sample tissue of cambium that wherein the A Hematorylin-Yihong dyeing shows; B is the immunohistochemical staining of anti-VIII factor antibody
Embodiment
Human amniotic membrane tissue-derived mesenchymal cells can separate by application for a patent for invention number 200610033007.9 disclosed methods, and the present invention separates to obtain as follows voluntarily.
One, remove amniotic epithelial cells:
1. after will fetching the laboratory with the Freshman amnion that physiological saline soaks, use 4 ℃ 0.9%NaCl (containing three resists: penicillin, Streptomycin sulphate and gentamicin) to clean rapidly.Do not have any impurity, bloodstain, put into the Sterile Saline bottle after washing with 0.9%NaCl then until the amnion two sides, send into aseptic.Amnion is put into three anti-liquid gives a baby a bath on the third day after its birth to place all over the back and wherein soaks 2h.Soaking the back uses D-hank ' s to wash 3-5 time.
2, amnion is cut into the about 1mm of fragment
3
3, change 50ml centrifuge tube or suitable containers over to, add the equal-volume 0.25%Trypsin (pancreatin) (final concentration is 0.125%) of D-hank ' s liquid dilution
4, place in the biological oscillator behind the mixing, 37 ℃ jolt 15min, rotating speed 100rpm
5, the centrifugal supernatant liquor of abandoning
6, the equal-volume 0.25%Trypsin (final concentration is 0.125%) and the mixing that add the dilution of D-hank ' s liquid
7,37 ℃ jolt 30min, rotating speed 400～600rpm
8, abandon suspension, collect amnion tissue
9, repeat 6～8 steps 2 time, remove amniotic epithelial cells fully.
Two, separation and purification amniotic mesenchymal cell
10, the rinsing of amnion tissue D-hank ' s liquid is clean;
11,0.1% collagenase III, IV and V (1: 1: the 1.5) mixed solution of fragment of tissue to prepare;
12,37 ℃ jolt 30min, rotating speed 400～600rpm;
13, the cell sieve filters suspension;
14, centrifugal collector's amniotic mesenchymal cell and counting are looked experiment situation repeating step 12-13;
Embodiment: treatment necrosis of femoral head experimental program
1, application organizes engineering science principle will contain hAMCs cell suspension (above-mentioned steps 13 obtains) and plant in going on the little ox bone of matrix (biological support), form hAMCs-and remove matrix calf bone compound.Cell concn limits (10 according to material volume
5-6Cell/cm
3)
2, hAMCs-goes interior transplanting of body of matrix calf bone compound.
(1) necrotic bone is struck off in conventional osteonecrosis operation, exposes normal bone tissues, forms the bone defect area.
(2) suppress hAMCs-is gone matrix calf bone compound implantable bone defect area.
(3) operation stitching.
3, hAMCs-goes matrix calf bone compound transplantation treatment dog femoral head defects
Use dog as animal pattern, the action effect of research human amniotic membrane tissue-derived mesenchymal cells (hAMCs) transplantation treatment femoral head defects.Experimental results show that hAMCs can fine reparation dog femoral head defects, the fine fusion of freshman bone tissue and receptor bone, the bone trabecula edge of freshman bone tissue is attached with the active scleroblast of a large amount of propagation, has the chondrocyte in the bone trabecula, and abundant vascular tissue is arranged on every side.See Fig. 1 and Fig. 2.
A is the gross anatomy sample that hAMCs-goes matrix calf bone transplantation treatment dog femoral head defects among Fig. 1, the white portion of yellow arrows indication is a graft among the figure, the hAMCs-at femoral head defects place takes off cell calf bone compound (yellow arrows), with the fine fusion one of receptor bone; B is that the indigo plant person of dying is area of new bone cell (Toluidine blue staining) among Fig. 1; C and D are that red colored part is the freshman bone tissue's (Hematorylin-Yihong dyeing) in the graft among Fig. 1, wherein D is the interior typical bone trabecula of yellow frame among Fig. 1, as seen the bone trabecula edge is attached with the active scleroblast of a large amount of propagation, have the chondrocyte in the bone trabecula, abundant vascular tissue is arranged on every side.E is the X line video of hAMCs transplantation treatment dog femoral head defects among Fig. 1, and the left side is a materials control, and good transmittance is black; The right side is an experimental group, and the transparence difference is canescence, and look arrow indication is the femoral head defects repair place.
A is blood vessel sample tissue in the cambium that Hematorylin-Yihong dyeing shows among Fig. 2, B is immunohistochemical staining (the DAB colour developing for anti-VIII factor antibody among Fig. 2, positive cell is a brown), the expression of a large amount of brown positive cells is arranged, the formation that prompting hAMCs-removes new vessel in the matrix calf bone compound around blood vessel sample tissue.
The action effect of proof hAMCs transplantation treatment femoral head defects is obvious.
Claims (3)
1. medicine for the treatment of osteonecrosis, its effective constituent is human amniotic membrane tissue-derived mesenchymal cells.
2. a cytoskeleton is characterized in that being attached with on this support the described medicine of claim 1, and described cytoskeletal material is for removing the little ox bone of matrix.
3. cytoskeleton according to claim 2, described human amniotic membrane tissue-derived mesenchymal cells concentration is 10
5-10
6/ 1cm
3
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| CN113181429A (en) * | 2021-04-26 | 2021-07-30 | 右江民族医学院附属医院 | Method for preparing plastic long-section bone repair material and bone tissue engineering scaffold with controllable slow release of bioactive factors |
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