脂肪间充质干细胞移植治疗兔急性心肌梗死的实验研究
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摘要
目的：1、探索脂肪间充质干细胞(ADMSCs)的分离、体外培养的方法。2、探讨同种异体移植ADMSCs在兔急性心肌梗死区存活并分化为心肌细胞的情况及对兔急性心肌梗死后心功能的影响。3、探讨脂肪间充质干细胞(ADMSC)移植对兔心肌梗死后微血管生成的可能机制及心功能的变化情况。
方法：1、ADMSCs的分离、培养及标记：无菌条件下获取兔腹部大网膜脂肪组织,采用Ⅰ型胶原酶消化法及贴壁法分离培养ADMSCs,并在体外持续传代培养,对第3代ADMSCs进行表面标志分子鉴定。取第3代细胞,用4’,6-二脒-2-苯基吲哚(4',6-diamidio-2-phenylindole, DAPI)标记,并在荧光显微镜下观察。2、ADMSCs移植在急性心肌梗死中的治疗：30只健康日本大耳白兔随机分为假手术组(n=10)、心肌梗死对照组以及ADMSCs移植组(n=10)。结扎兔前室间支,建立急性心肌梗死动物模型,AMIlh内将DAPI标记的第三代ADMSCs (5×106个,1ml)植入ADMSCs移植组梗死心肌,对照组及假手术组注射等量PBS液。术前及术后4周分别做超声心动图检查其心功能变化。取心梗区组织作冰冻切片,荧光显微镜下验证移植后的ADMSCs是否向心肌细胞分化,HE染色和CD34免疫组化观察梗死区毛细血管新生情况,采用半定量RT-PCR检测梗死区VEGF和bFGF的表达。
结果：1、兔脂肪组织中含有大量间充质干细胞,并易于分离、培养,流式细胞仪鉴定CD44、CD71阳性表达,CD34、CD45阴性表达。接种24h后,体积较大的细胞很多已贴壁,48h后贴壁细胞开始分裂增殖,5-7天后,培养皿底细胞融合达80%。传代后细胞形态渐趋一致,呈长梭形,以一点为中心向四周放射状排列,圆形或卵圆形混杂生长细胞随换液及传代次数增加,逐渐减少。荧光显微镜下观察DAPI标记的第3代ADMSCs,标记率几乎达100%。2.超声心动图检测证实移植后4周ADMSCs组左室收缩末期直径、舒张末期直径均小于AMI对照组(均p<0.05),与左心室重量指数结果相同(p<0.05),而短轴缩短率、射血分数均大于对照组(均p<0.05)；ADMSCs移植组荧光显微镜下可以观察到DAPI标记细胞存在,并分化为心肌样细胞。3.CD34免疫组化染色显示ADMSCs组梗死局部毛细血管密度明显高于对照组(p<0.05),RT-PCR结果显示ADMSCs组VEGF和bFGF的表达水平较AMI对照组明显增高(p<0.05)。
结论：1.建立了一种自兔脂肪组织分离、培养及高效标记ADMSCs经济简便的方法。2.同种异体移植的ADMSCs能够在梗死心肌内存活并分化为心肌样细胞,增加梗死区血管新生,抑制心室重构、改善心肌梗死后心功能。3. ADMSCs移植促进心肌梗死区微血管的生成,并改善心脏功能,其机制可能与促进bFGF. VEGF的表达有关。
Objective:1.To explore the method for isolation and cultivation of adipose tissue-derived mesenchymal stem cells(ADMSCs).2.To confirm that ADMSCs can survive,differentiate into cardiomyocyte-like cells in vivo,and improve heart function.3. To investigate the possible mechanisms of adipose tissue-derived mesenchymal stem cells(ADMSCs) transplantation on the angiogenesis in myocardial infarction rabbits.
Methods:1.Isolating,culturing and labelling ADMSCs.The adipose tissue was o-btained from the epiloon of rabbits under the aseptic condition.ADMSCs were isolate-d by the method of digesting with typeⅠcollagenase and adereing to the culture flas-k,and continuely cultured in vitro. The third passage of ADMSCs were used to ident-ify surface molecular marks. The third passage were labelled by DAPI,and then obse-rved by fluoresecent microscope.2.Treatment after acute myocardial infarction with ADMSCs transplantation.30 rabbits are randomly divided into three groups:shame operation with PBS injection(sham group,n=10),heart infarcted model with PBS inje- ction(control group.n=10),heart infarcted model with ADMSCs group (ADMSCs group,n=10). The third passage of ADMSCs labelled by DAPI were injected into the center and the border of the MI area after AMI 1h.The same volume of PBS was inje-cted into the MI area of the control group and sham group. Echocardiography was pe-rformed to evaluate the cardiac function before operation and 4 weeks after MI.After 4 weeks,the hearts were harvested.The presence of labelled cells was confirmed by fl-uorescent microscope,and differentiation of the labelled cells were observed by immu-nohistochemical stain of c TnI.The infarcted area were sectioned for HE stain and cap-illary were sectioned for immunohistochemical stain of CD34. The expression of V-EGF and bFGF in ischemic region were detected with RT-PCR.
Results:1.Rabbits adipose tissue contained a great quantity of mesenchymal stem cells,which were quite easy to isolate and culture.24h after inoculation,many bigger cells had been adheret to the tisse culture flask.After 48h,the cells began to proliferate,after 5-7 d-ay, cells reached 80%confluence. After the passage,ADMSCs appeared to adopt a m-ore uniform fibroblast-like shape with directionality and regularity, similar to bone mar-row stromal cells.The round or oval cells decreased with the exchanging the media and passage. CD71nd CD44 were all positive in these cells,but CD34 and CD45 were negative. The marked rate of the third passage of ADMSCs labelled by DAPI was almost 100%under fluor-escent microscope.2. Compared with AMI control group,4 weeks after implantation ADMSCs group resulted in shorter LVIDd,LVIDs, and higher FS,EF(p<0.05).The la-belled cells were visible in the recipient heart,and some of them differentiated into ca-rdiac muscle(p<0.05).3. The microvessal density in the infarction regions treated with ADMSCs was higher than that in AMI group.The expression of bFGF and VEGF in t-he myocardial tissue of ADMSCs group was higher than that in AMI group and cont-rol group(p<0.05).
Conclusion:1.In our study,an economic,simply and efficient way to isolate, cult-ure and labelling of ADMSCs from rabbit adipose tissue is established.2. Transplanta-tion allograftic ADMSCs can survive and differentiate into cardiomyocyte,promote angiogenesis in the infarcted or ischemic area of myocardium,and improve the heart function after MI.3. The transplantation of ADMSCs can promote the revasculariza- tion in infarcted regions, and improve the heart function by enhancing VEGF and bFGF synthesis.
方法：1、ADMSCs的分离、培养及标记：无菌条件下获取兔腹部大网膜脂肪组织,采用Ⅰ型胶原酶消化法及贴壁法分离培养ADMSCs,并在体外持续传代培养,对第3代ADMSCs进行表面标志分子鉴定。取第3代细胞,用4’,6-二脒-2-苯基吲哚(4',6-diamidio-2-phenylindole, DAPI)标记,并在荧光显微镜下观察。2、ADMSCs移植在急性心肌梗死中的治疗：30只健康日本大耳白兔随机分为假手术组(n=10)、心肌梗死对照组以及ADMSCs移植组(n=10)。结扎兔前室间支,建立急性心肌梗死动物模型,AMIlh内将DAPI标记的第三代ADMSCs (5×106个,1ml)植入ADMSCs移植组梗死心肌,对照组及假手术组注射等量PBS液。术前及术后4周分别做超声心动图检查其心功能变化。取心梗区组织作冰冻切片,荧光显微镜下验证移植后的ADMSCs是否向心肌细胞分化,HE染色和CD34免疫组化观察梗死区毛细血管新生情况,采用半定量RT-PCR检测梗死区VEGF和bFGF的表达。
结果：1、兔脂肪组织中含有大量间充质干细胞,并易于分离、培养,流式细胞仪鉴定CD44、CD71阳性表达,CD34、CD45阴性表达。接种24h后,体积较大的细胞很多已贴壁,48h后贴壁细胞开始分裂增殖,5-7天后,培养皿底细胞融合达80%。传代后细胞形态渐趋一致,呈长梭形,以一点为中心向四周放射状排列,圆形或卵圆形混杂生长细胞随换液及传代次数增加,逐渐减少。荧光显微镜下观察DAPI标记的第3代ADMSCs,标记率几乎达100%。2.超声心动图检测证实移植后4周ADMSCs组左室收缩末期直径、舒张末期直径均小于AMI对照组(均p<0.05),与左心室重量指数结果相同(p<0.05),而短轴缩短率、射血分数均大于对照组(均p<0.05)；ADMSCs移植组荧光显微镜下可以观察到DAPI标记细胞存在,并分化为心肌样细胞。3.CD34免疫组化染色显示ADMSCs组梗死局部毛细血管密度明显高于对照组(p<0.05),RT-PCR结果显示ADMSCs组VEGF和bFGF的表达水平较AMI对照组明显增高(p<0.05)。
结论：1.建立了一种自兔脂肪组织分离、培养及高效标记ADMSCs经济简便的方法。2.同种异体移植的ADMSCs能够在梗死心肌内存活并分化为心肌样细胞,增加梗死区血管新生,抑制心室重构、改善心肌梗死后心功能。3. ADMSCs移植促进心肌梗死区微血管的生成,并改善心脏功能,其机制可能与促进bFGF. VEGF的表达有关。
Objective:1.To explore the method for isolation and cultivation of adipose tissue-derived mesenchymal stem cells(ADMSCs).2.To confirm that ADMSCs can survive,differentiate into cardiomyocyte-like cells in vivo,and improve heart function.3. To investigate the possible mechanisms of adipose tissue-derived mesenchymal stem cells(ADMSCs) transplantation on the angiogenesis in myocardial infarction rabbits.
Methods:1.Isolating,culturing and labelling ADMSCs.The adipose tissue was o-btained from the epiloon of rabbits under the aseptic condition.ADMSCs were isolate-d by the method of digesting with typeⅠcollagenase and adereing to the culture flas-k,and continuely cultured in vitro. The third passage of ADMSCs were used to ident-ify surface molecular marks. The third passage were labelled by DAPI,and then obse-rved by fluoresecent microscope.2.Treatment after acute myocardial infarction with ADMSCs transplantation.30 rabbits are randomly divided into three groups:shame operation with PBS injection(sham group,n=10),heart infarcted model with PBS inje- ction(control group.n=10),heart infarcted model with ADMSCs group (ADMSCs group,n=10). The third passage of ADMSCs labelled by DAPI were injected into the center and the border of the MI area after AMI 1h.The same volume of PBS was inje-cted into the MI area of the control group and sham group. Echocardiography was pe-rformed to evaluate the cardiac function before operation and 4 weeks after MI.After 4 weeks,the hearts were harvested.The presence of labelled cells was confirmed by fl-uorescent microscope,and differentiation of the labelled cells were observed by immu-nohistochemical stain of c TnI.The infarcted area were sectioned for HE stain and cap-illary were sectioned for immunohistochemical stain of CD34. The expression of V-EGF and bFGF in ischemic region were detected with RT-PCR.
Results:1.Rabbits adipose tissue contained a great quantity of mesenchymal stem cells,which were quite easy to isolate and culture.24h after inoculation,many bigger cells had been adheret to the tisse culture flask.After 48h,the cells began to proliferate,after 5-7 d-ay, cells reached 80%confluence. After the passage,ADMSCs appeared to adopt a m-ore uniform fibroblast-like shape with directionality and regularity, similar to bone mar-row stromal cells.The round or oval cells decreased with the exchanging the media and passage. CD71nd CD44 were all positive in these cells,but CD34 and CD45 were negative. The marked rate of the third passage of ADMSCs labelled by DAPI was almost 100%under fluor-escent microscope.2. Compared with AMI control group,4 weeks after implantation ADMSCs group resulted in shorter LVIDd,LVIDs, and higher FS,EF(p<0.05).The la-belled cells were visible in the recipient heart,and some of them differentiated into ca-rdiac muscle(p<0.05).3. The microvessal density in the infarction regions treated with ADMSCs was higher than that in AMI group.The expression of bFGF and VEGF in t-he myocardial tissue of ADMSCs group was higher than that in AMI group and cont-rol group(p<0.05).
Conclusion:1.In our study,an economic,simply and efficient way to isolate, cult-ure and labelling of ADMSCs from rabbit adipose tissue is established.2. Transplanta-tion allograftic ADMSCs can survive and differentiate into cardiomyocyte,promote angiogenesis in the infarcted or ischemic area of myocardium,and improve the heart function after MI.3. The transplantation of ADMSCs can promote the revasculariza- tion in infarcted regions, and improve the heart function by enhancing VEGF and bFGF synthesis.
引文
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1. Zuk PA, Zhu M,Mizuno H, et al:Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001; 7:211-228
2. Gronthos S, Franklin DM,Leddy HA, et al:Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol 2001; 189:54-63
3. Aust L, Devlin B,Foster SJ, et al:Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy 2004; 6:7-14
4. Dawn B,Bolli R:Adult bone marrow-derived cells:regenerative potential, plasticity, and tissue commitment. Basic Res Cardiol 2005; 100:494-503
5. Parker AM,Katz AJ:Adipose-derived stem cells for the regeneration of damaged tissues. Expert Opin Biol Ther 2006; 6:567-578
6. Zhu Y, Liu T,Song K, et al:Adipose-derived stem cell:a better stem cell than BMSC. Cell Biochem Funct 2008; 26:664-675
7. Planat-Benard V, Silvestre JS,Cousin B, et al:Plasticity of human adipose lineage cells toward endothelial cells:physiological and therapeutic perspectives. Circulation 2004; 109:656-663
8. De UD, Morizono K,Elbarbary A, et al:Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs 2003; 174:101-109
9. Mitchell JB, McIntosh K,Zvonic S, et al:Immunophenotype of human adipose-derived cells:temporal changes in stromal-associated and stem cell-associated markers. Stem Cells 2006; 24:376-385
10. Oedayrajsingh-Varma MJ, van HS,Knippenberg M, et al:Adipose tissue-derived mesenchymal stem cell yield and growth characteristics are affected by the tissue-harvesting procedure. Cytotherapy 2006; 8:166-177
11. Fraser JK, Schreiber RE,Zuk PA, et al:Adult stem cell therapy for the heart. Int J Biochem Cell Biol 2004; 36:658-666
12. Levesque JP, Takamatsu Y,Nilsson SK, et al:Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor. Blood 2001; 98:1289-1297
13. Zuk PA, Zhu M,Ashjian P, et al:Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002; 13:4279-4295
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[2]Wang J S, Shum-Tim D, Galipeau J, et al. Marrow stromal cells for cellular cardiomyoplasty:feasibility and potential clinical advantages.[J]. J Thorac Cardiovasc Surg,2000,120(5):999-1005.
[3]Wakitani S, Saito T, Caplan A I. Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine.[J]. Muscle Nerve,1995,18(12):1417-1426.
[4]Zuk P A, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies.[J]. Tissue Eng,2001,7(2):211-228.
[5]Gronthos S, Franklin D M, Leddy H A, et al. Surface protein characterization of human adipose tissue-derived stromal cells.[J]. J Cell Physiol,2001,189(1):54-63.
[6]Aust L, Devlin B, Foster S J, et al. Yield of human adipose-derived adult stem cells from liposuction aspirates.[J]. Cytotherapy,2004,6(1):7-14.
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[10]de Ugarte D A, Morizono K, Elbarbary A, et al. Comparison of multi-lineage cells from human adipose tissue and bone marrow.[J]. Cells Tissues Organs,2003,174(3):101-109.
[11]Gaustad K G, Boquest A C, Anderson B E, et al. Differentiation of human adipose tissue stem cells using extracts of rat cardiomyocytes.[J]. Biochem Biophys Res Commun,2004,314(2):420-427.
[12]张卫泽,樊艳,陈永清,等血管紧张素Ⅱ对成人脂肪间充质干细胞向心肌细胞分化的影响[J].第四军医大学学报,2008,29(8)：692-695.
[13]Fukuhara S, Tomita S, Yamashiro S, et al. Direct cell-cell interaction of cardiomyocytes is key for bone marrow stromal cells to go into cardiac lineage in vitro.[J]. J Thorac Cardiovasc Surg,2003,125(6):1470-1480.
[14]Toma C, Pittenger M F, Cahill K S, et al. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart.[J]. Circulation,2002,105(1):93-98.
[15]Burashnikov A, Antzelevitch C. Block of I(Ks) does not induce early afterdepolarization activity but promotes beta-adrenergic agonist-induced delayed afterdepolarization activity.[J]. J Cardiovasc Electrophysiol,2000,11(4):458-465
[16]Valina C, Pinkernell K, Song Y H, et al. Intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction.[J]. Eur Heart J,2007,28(21):2667-2677.
[1]Zuk P A, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells.[J]. Mol Biol Cell.2002,13(12):4279-4295.
[2]Planat-Benard V, Silvestre J S, Cousin B, et al. Plasticity of human adipose lineage cells toward endothelial cells:physiological and therapeutic perspectives.[J]. Circulation.2004,109(5):656-663.
[3]Valina C, Pinkernell K, Song Y H, et al. Intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction.[J]. Eur Heart J.2007, 28(21):2667-2677.
[4]Nakagami H, Maeda K, Morishita R, et al. Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells.[J]. Arterioscler Thromb Vasc Biol.2005,25(12): 2542-2547.
[5]Traktuev D O, Parfenova E V, Tkachuk V A, et al. Adipose stromal cells--plastic type of cells with high therapeutic potential.[J]. Tsitologiia.2006,48(2):83-94.
[6]Miyahara Y, Nagaya N, Kataoka M, et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction.[J]. Nat Med.2006,12(4): 459-465.
[7]Sorop O, Merkus D, de Beer V J, et al. Functional and structural adaptations of coronary microvessels distal to a chronic coronary artery stenosis.[J]. Circ Res.2008, 102(7):795-803.
[8]Li S R, Qi X Y, Hu F L, et al. Mechanisms of improvement of left ventricle remodeling by trans-planting two kinds of autologous bone marrow stem cells in pigs.[J]. Chin Med J (Engl).2008,121(23):2403-2409.
[9]王杰华,刘楠,杜厚伟,翁金森,等.脂肪来源的干细胞移植对大鼠脑缺血后微血管生成及bFGF和VEGF表达的影响[J].细胞与分子免疫学杂志,2008,24(10)：958-961
[10]Kurmasheva R T, Harwood F C, Houghton P J. Differential regulation of vascular endothelial growth factor by Akt and mammalian target of rapamycin inhibitors in cell lines derived from childhood solid tumors.[J]. Mol Cancer Ther. 2007,6(5):1620-1628.
[11]Rosenblatt-Velin N, Lepore M G, Cartoni C, et al. FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes.[J]. J Clin Invest.2005,115(7):1724-1733.
[12]Pons J, Huang Y, Arakawa-Hoyt J, et al. VEGF improves survival of mesenchymal stem cells in infarcted hearts. [J]. Epub.2008,376(2):419-22.
[13]Memon I A, Sawa Y, Miyagawa S, et al. Combined autologous cellular cardiomyoplasty with skeletal myoblasts and bone marrow cells in canine hearts for ischemic cardiomyopathy.[J]. J Thorac Cardiovasc Surg.2005,130(3):646-653.
[14]Li Z, Wilson K D, Smith B, et al. Functional and transcriptional characterization of human embryonic stem cell-derived endothelial cells for treatment of myocardial infarction.[J]. PLoS One.2009,4(12):e8443.
1.Kajstura J, Leri A,Finato N, et al:Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci U S A 1998; 95:8801-8805
2. Soonpaa MH,Field LJ:Survey of studies examining mammalian cardiomyocyte DNA synthesis. Circ Res 1998; 83:15-26
3. Reinecke H, Poppa V,Murry CE:Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting. J Mol Cell Cardiol 2002; 34:241-249
4. Eisen HJ:Skeletal myoblast transplantation:no MAGIC bullet for ischemic cardiomyopathy. Nat Clin Pract Cardiovasc Med 2008; 5:520-521
5. Makhluf HA, Mueller SM,Mizuno S, et al:Age-related decline in osteoprotegerin expression by human bone marrow cells cultured in three-dimensional collagen sponges. Biochem Biophys Res Commun 2000; 268:669-672
6. Zuk PA, Zhu M,Mizuno H, et al:Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001; 7:211-228
7. Gronthos S, Simmons PJ,Graves SE, et al:Integrin-mediated interactions between human bone marrow stromal precursor cells and the extracellular matrix. Bone 2001; 28:174-181
8. Aust L, Devlin B,Foster SJ, et al:Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy 2004; 6:7-14
9. Jackson KA, Mi T,Goodell MA:Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc Natl Acad Sci U S A 1999; 96:14482-14486
10. Dawn B,Bolli R:Adult bone marrow-derived cells:regenerative potential, plasticity, and tissue commitment. Basic Res Cardiol 2005; 100:494-503
11. Parker AM,Katz AJ:Adipose-derived stem cells for the regeneration of damaged tissues. Expert Opin Biol Ther 2006; 6:567-578
12. Zuk PA, Zhu M,Ashjian P, et al:Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002; 13:4279-4295
13. De UD, Alfonso Z,Zuk PA, et al:Differential expression of stem cell mobilization-associated molecules on multi-lineage cells from adipose tissue and bone marrow. Immunol Lett 2003; 89:267-270
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18. Oedayrajsingh-Varma MJ, van HS,Knippenberg M, et al:Adipose tissue-derived mesenchymal stem cell yield and growth characteristics are affected by the tissue-harvesting procedure. Cytotherapy 2006; 8:166-177
19. Fraser JK, Schreiber RE,Zuk PA, et al:Adult stem cell therapy for the heart. Int J Biochem Cell Biol 2004; 36:658-666
20. Levesque JP, Takamatsu Y,Nilsson SK, et al:Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor. Blood 2001; 98:1289-1297
21. Rehman J, Traktuev D,Li J, et al:Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 2004; 109:1292-1298
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31. Fukuhara S, Tomita S,Yamashiro S, et al:Direct cell-cell interaction of cardiomyocytes is key for bone marrow stromal cells to go into cardiac lineage in vitro. J Thorac Cardiovasc Surg 2003; 125:1470-1480
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8. Gronthos S, Franklin DM,Leddy HA, et al:Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol 2001; 189:54-63
9. Aust L, Devlin B,Foster SJ, et al:Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy 2004; 6:7-14
10. Zhu Y, Liu T,Song K, et al:Adipose-derived stem cell:a better stem cell than BMSC. Cell Biochem Funct 2008; 26:664-675
11. Zuk PA, Zhu M,Ashjian P, et al:Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002; 13:4279-4295
12. Planat-Benard V, Silvestre JS,Cousin B, et al:Plasticity of human adipose lineage cells toward endothelial cells:physiological and therapeutic perspectives. Circulation 2004; 109:656-663
13. De UD, Morizono K,Elbarbary A, et al:Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs 2003; 174:101-109
14. Lei L, Liao W,Sheng P, et al:Biological character of human adipose-derived adult stem cells and influence of donor age on cell replication in culture. Sci China C Life Sci 2007; 50:320-328
15. Mitchell JB, McIntosh K,Zvonic S, et al:Immunophenotype of human adipose-derived cells:temporal changes in stromal-associated and stem cell-associated markers. Stem Cells 2006; 24:376-385
16. Oedayrajsingh-Varma MJ, van HS,Knippenberg M, et al:Adipose tissue-derived mesenchymal stem cell yield and growth characteristics are affected by the tissue-harvesting procedure. Cytotherapy 2006; 8:166-177
17. Fraser JK, Schreiber RE,Zuk PA, et al:Adult stem cell therapy for the heart. Int J Biochem Cell Biol 2004; 36:658-666
18. Levesque JP, Takamatsu Y,Nilsson SK, et al:Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor. Blood 2001; 98:1289-1297
19. Rehman J, Traktuev D,Li J, et al:Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 2004; 109:1292-1298
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37. Valina C, Pinkernell K,Song YH, et al:Intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction. Eur Heart J 2007; 28:2667-2677
38. Mazo M, Planat-Benard V,Abizanda G, et al:Transplantation of adipose derived stromal cells is associated with functional improvement in a rat model of chronic myocardial infarction. Eur J Heart Fail 2008; 10:454-462
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44. Miyahara Y, Nagaya N,Kataoka M, et al:Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med 2006; 12:459-465。
45.王杰华,刘楠,杜厚伟,翁金森,等.脂肪来源的干细胞移植对大鼠脑缺血后微血管生成及bFGF和VEGF表达的影响[J].细胞与分子免疫学杂志,2008,24(10)：958-961。
1. Zuk PA, Zhu M,Mizuno H, et al:Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001; 7:211-228
2. Gronthos S, Franklin DM,Leddy HA, et al:Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol 2001; 189:54-63
3. Aust L, Devlin B,Foster SJ, et al:Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy 2004; 6:7-14
4. Dawn B,Bolli R:Adult bone marrow-derived cells:regenerative potential, plasticity, and tissue commitment. Basic Res Cardiol 2005; 100:494-503
5. Parker AM,Katz AJ:Adipose-derived stem cells for the regeneration of damaged tissues. Expert Opin Biol Ther 2006; 6:567-578
6. Zhu Y, Liu T,Song K, et al:Adipose-derived stem cell:a better stem cell than BMSC. Cell Biochem Funct 2008; 26:664-675
7. Planat-Benard V, Silvestre JS,Cousin B, et al:Plasticity of human adipose lineage cells toward endothelial cells:physiological and therapeutic perspectives. Circulation 2004; 109:656-663
8. De UD, Morizono K,Elbarbary A, et al:Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs 2003; 174:101-109
9. Mitchell JB, McIntosh K,Zvonic S, et al:Immunophenotype of human adipose-derived cells:temporal changes in stromal-associated and stem cell-associated markers. Stem Cells 2006; 24:376-385
10. Oedayrajsingh-Varma MJ, van HS,Knippenberg M, et al:Adipose tissue-derived mesenchymal stem cell yield and growth characteristics are affected by the tissue-harvesting procedure. Cytotherapy 2006; 8:166-177
11. Fraser JK, Schreiber RE,Zuk PA, et al:Adult stem cell therapy for the heart. Int J Biochem Cell Biol 2004; 36:658-666
12. Levesque JP, Takamatsu Y,Nilsson SK, et al:Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor. Blood 2001; 98:1289-1297
13. Zuk PA, Zhu M,Ashjian P, et al:Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002; 13:4279-4295
[1]Beltrami A P, Urbanek K, Kajstura J, et al. Evidence that human cardiac myocytes divide after myocardial infarction.[J]. N Engl J Med,2001,344(23):1750-1757.
[2]Wang J S, Shum-Tim D, Galipeau J, et al. Marrow stromal cells for cellular cardiomyoplasty:feasibility and potential clinical advantages.[J]. J Thorac Cardiovasc Surg,2000,120(5):999-1005.
[3]Wakitani S, Saito T, Caplan A I. Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine.[J]. Muscle Nerve,1995,18(12):1417-1426.
[4]Zuk P A, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies.[J]. Tissue Eng,2001,7(2):211-228.
[5]Gronthos S, Franklin D M, Leddy H A, et al. Surface protein characterization of human adipose tissue-derived stromal cells.[J]. J Cell Physiol,2001,189(1):54-63.
[6]Aust L, Devlin B, Foster S J, et al. Yield of human adipose-derived adult stem cells from liposuction aspirates.[J]. Cytotherapy,2004,6(1):7-14.
[7]Kajstura J, Leri A, Finato N, et al. Myocyte proliferation in end-stage cardiac failure in humans.[J]. Proc Natl Acad Sci U S A,1998,95(15):8801-8805.
[8]Soonpaa M H, Field L J. Survey of studies examining mammalian cardiomyocyte DNA synthesis.[J]. Circ Res,1998,83(1):15-26.
[9]Tomita S, Li R K, Weisel R D, et al. Autologous transplantation of bone marrow cells improves damaged heart function.[J]. Circulation,1999,100(19 Suppl):I247-I256.
[10]de Ugarte D A, Morizono K, Elbarbary A, et al. Comparison of multi-lineage cells from human adipose tissue and bone marrow.[J]. Cells Tissues Organs,2003,174(3):101-109.
[11]Gaustad K G, Boquest A C, Anderson B E, et al. Differentiation of human adipose tissue stem cells using extracts of rat cardiomyocytes.[J]. Biochem Biophys Res Commun,2004,314(2):420-427.
[12]张卫泽,樊艳,陈永清,等血管紧张素Ⅱ对成人脂肪间充质干细胞向心肌细胞分化的影响[J].第四军医大学学报,2008,29(8)：692-695.
[13]Fukuhara S, Tomita S, Yamashiro S, et al. Direct cell-cell interaction of cardiomyocytes is key for bone marrow stromal cells to go into cardiac lineage in vitro.[J]. J Thorac Cardiovasc Surg,2003,125(6):1470-1480.
[14]Toma C, Pittenger M F, Cahill K S, et al. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart.[J]. Circulation,2002,105(1):93-98.
[15]Burashnikov A, Antzelevitch C. Block of I(Ks) does not induce early afterdepolarization activity but promotes beta-adrenergic agonist-induced delayed afterdepolarization activity.[J]. J Cardiovasc Electrophysiol,2000,11(4):458-465
[16]Valina C, Pinkernell K, Song Y H, et al. Intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction.[J]. Eur Heart J,2007,28(21):2667-2677.
[1]Zuk P A, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells.[J]. Mol Biol Cell.2002,13(12):4279-4295.
[2]Planat-Benard V, Silvestre J S, Cousin B, et al. Plasticity of human adipose lineage cells toward endothelial cells:physiological and therapeutic perspectives.[J]. Circulation.2004,109(5):656-663.
[3]Valina C, Pinkernell K, Song Y H, et al. Intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction.[J]. Eur Heart J.2007, 28(21):2667-2677.
[4]Nakagami H, Maeda K, Morishita R, et al. Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells.[J]. Arterioscler Thromb Vasc Biol.2005,25(12): 2542-2547.
[5]Traktuev D O, Parfenova E V, Tkachuk V A, et al. Adipose stromal cells--plastic type of cells with high therapeutic potential.[J]. Tsitologiia.2006,48(2):83-94.
[6]Miyahara Y, Nagaya N, Kataoka M, et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction.[J]. Nat Med.2006,12(4): 459-465.
[7]Sorop O, Merkus D, de Beer V J, et al. Functional and structural adaptations of coronary microvessels distal to a chronic coronary artery stenosis.[J]. Circ Res.2008, 102(7):795-803.
[8]Li S R, Qi X Y, Hu F L, et al. Mechanisms of improvement of left ventricle remodeling by trans-planting two kinds of autologous bone marrow stem cells in pigs.[J]. Chin Med J (Engl).2008,121(23):2403-2409.
[9]王杰华,刘楠,杜厚伟,翁金森,等.脂肪来源的干细胞移植对大鼠脑缺血后微血管生成及bFGF和VEGF表达的影响[J].细胞与分子免疫学杂志,2008,24(10)：958-961
[10]Kurmasheva R T, Harwood F C, Houghton P J. Differential regulation of vascular endothelial growth factor by Akt and mammalian target of rapamycin inhibitors in cell lines derived from childhood solid tumors.[J]. Mol Cancer Ther. 2007,6(5):1620-1628.
[11]Rosenblatt-Velin N, Lepore M G, Cartoni C, et al. FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes.[J]. J Clin Invest.2005,115(7):1724-1733.
[12]Pons J, Huang Y, Arakawa-Hoyt J, et al. VEGF improves survival of mesenchymal stem cells in infarcted hearts. [J]. Epub.2008,376(2):419-22.
[13]Memon I A, Sawa Y, Miyagawa S, et al. Combined autologous cellular cardiomyoplasty with skeletal myoblasts and bone marrow cells in canine hearts for ischemic cardiomyopathy.[J]. J Thorac Cardiovasc Surg.2005,130(3):646-653.
[14]Li Z, Wilson K D, Smith B, et al. Functional and transcriptional characterization of human embryonic stem cell-derived endothelial cells for treatment of myocardial infarction.[J]. PLoS One.2009,4(12):e8443.
1.Kajstura J, Leri A,Finato N, et al:Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci U S A 1998; 95:8801-8805
2. Soonpaa MH,Field LJ:Survey of studies examining mammalian cardiomyocyte DNA synthesis. Circ Res 1998; 83:15-26
3. Reinecke H, Poppa V,Murry CE:Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting. J Mol Cell Cardiol 2002; 34:241-249
4. Eisen HJ:Skeletal myoblast transplantation:no MAGIC bullet for ischemic cardiomyopathy. Nat Clin Pract Cardiovasc Med 2008; 5:520-521
5. Makhluf HA, Mueller SM,Mizuno S, et al:Age-related decline in osteoprotegerin expression by human bone marrow cells cultured in three-dimensional collagen sponges. Biochem Biophys Res Commun 2000; 268:669-672
6. Zuk PA, Zhu M,Mizuno H, et al:Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001; 7:211-228
7. Gronthos S, Simmons PJ,Graves SE, et al:Integrin-mediated interactions between human bone marrow stromal precursor cells and the extracellular matrix. Bone 2001; 28:174-181
8. Aust L, Devlin B,Foster SJ, et al:Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy 2004; 6:7-14
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