Dose-Dependent Relationship of Bone Marrow Mesenchymal Stem Cells Transplantation to Cardiomyogenesis for Functional Regenerative Recovery after Myocardial Infarction_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

ZHANG Leiyang , CHEN Xin , XU Shunlin

Department of Thoracic and Cardiovascular Surgery, Nanjing Cardiovascular Disease Research Institute, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing 210006, P.R.China Corresponding author: CHEN Xin, E-mail: stevecx@jlonline.com;

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Keywords：

Bone marrow mesenchymal stem cells; Cell transplantation; Myocardial ischemia; Cell dosage

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Objective To investigate the dose-dependent relationship of bone marrow mesenchymal stem cells(MSCs) transplantation in improving ischemic myocardial dysfunction? in a rat ischemic heart model. Methods Myocardial infarction was induced in 32 inbred F344 rats by acute ligation of the left anterior descending(LAD) coronary artery. One week after ligation, the ratswere randomized? into four equal groups, with eight rats in each group. Equal volume Iscove’s modified Dulbecco’s medium was injected in the control group, 1×103(group 1), 1×105(group 2), and 1×107(group 3) 5-bromodeoxyuridine (BrdU) labeled bone marrow MSCs were injected into the infarcted myocardium. Cardiac function was evaluated by ultrasound before the ligation of the LAD, before the transplantation and the 4th week after transplantation. The expressions of BrdU,Connexin43,Myosin heavy chain β(MHC), and smooth muscle actin α(α-SMA) were detected by immunofluorescence and immunohistochemistry at the 4th week after transplantation. The amount of functional vessels stained by α-SMA was counted simultaneously. Results At the 4th week? after transplantation, the ejection fraction(EF) in goup 2 was more significantly improved than that in group1(0.54±0.20 vs. 0.34±0.16, P＝0.004) and EF in group 3 was more significantly improved than that in group 2(0.71±0.24 vs. 0.54±0.20,P＝0.018), whereas no significant difference between group 1 and control group was detected (0.34±0.16 vs. 0.36±0.15,P gt;0.05). The BrdU labeled MSCs could be found in host myocardium. The number of cells in group 2 by double staining both for BrdU and for MHC observed in ischemic myocardium were significantly more than that in group 1? (323.20±91.62 n/HP vs. 51.75±27.58 n/HP,P＝0.049) and the same was true between group 3 and group 2(409.75±106.65 n/HP vs. 323.20±91.62 n/HP,P lt;0.001), whereas the result of control group was negative.The majority of transplanted cells were found positive staining both for MHC and for Connexin43 in all groups. There were lots of positive staining of α-SMA whose form were partly irregular in ischemic myocardium indicating that there was neovascularization in group1 and control group. More neovascularization in group2 was found than that in group 1 (28.38±12.79 n/HP vs. 22.75±9.07 n/HP, P＝0015) and more neovascularization in group 3 was found? than that in group 2 (35.63±13.27 n/HP vs. 28.38±12.79 n/HP, P＝0.002) . Conclusion Transplanted into infarcted myocardium, bone marrow MSCs may have significant and dose-dependent potential for cardiomyogenesis with functional recovery from myocardial ischemia.

Citation： ZHANG Leiyang,CHEN Xin,XU Shunlin,ZHUANG Yu,ZHU Changle. Dose-Dependent Relationship of Bone Marrow Mesenchymal Stem Cells Transplantation to Cardiomyogenesis for Functional Regenerative Recovery after Myocardial Infarction. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2007, 14(6): 447-. doi: Copy

1.	Orlic D, Kajstura J, Chimenti S, et al.Bone marrow cells regenerate infarcted myocardium. Nature, 2001, 410 (6829) :701-705.
2.	朱洪生,黄日太,连锋,等.骨髓间质干细胞移植对香猪急性心肌梗死后心肌结构和心功能的影响.中国胸心血管外科临床杂志,2004,11(2):112-115.
3.	连锋,朱洪生,薛松,等. 自体内皮祖细胞移植对急性心肌梗死近、中期心肌收缩力的影响. 中国胸心血管外科临床杂志,2006,13(5):326-330.
4.	Agbulut O, Menot ML, Li Z, et al. Temporal patterns of bone marrow cell differentiation following transplantation in doxorubicin-induced cardiomyopathy. Cardiovasc Res,2003, 58(2):451-459.
5.	Behfar A,Terzic A. Derivation of a cardiopoietic population from human mesenchymal stem cells yields cardiac progeny. Nat Clin Pract Cardiovasc Med,2006,3(Suppl 1):S78-S82.
6.	Briguori C, Reimers B, Sarais C, et al. Direct intramyocardial percutaneous delivery of autologous bone marrow in patients with refractory myocardial angina. Am Heart J, 2006,151(3):674-680.
7.	Bittira B, Kuang JQ, Al-Khaldi A, et al. In vitro preprogramming of marrow stromal cells for myocardial regeneration. Ann Thorac Surg, 2002,74(4):1154-1159.
8.	Rangappa S, Entwistle J, Wechsler AS, et al. Cardiomyocyte-mediated contact programs human mesenchymal stem cells to express cardiogenic phenotype. J Thorac Cardiovasc Surg,2003, 126(1):124-132.
9.	Shake JG, Gruber PJ, Baumgartner WA, et al. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg, 2002, 73(6):1919-1925.
10.	Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation, 2002, 106(15):1913-1918.
11.	Assmus B, Schchinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation, 2002, 106(24):3009-3017.
12.	Wang JS, Shun-Tim D, Galipeau J, et al. Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages. J Thorac Cardiovasc Surg, 2000, 120(5):999-1005.
13.	Zhang S, Wang D, Estrov Z, et al. Both cell fusion and transdifferentiation account for the transformation of human peripheral blood CD34-positive cells into cardiomyocytes in vivo. Circulation, 2004,110(25):3803-3807.
14.	Anderson DJ, Gage FH, Weissman IL.Can stem cells cross lineage boundaries? Nat Med, 2001, 7(4):393-395.
15.	Matsumoto K, Yoshitomi H, Rossant J, et al. Liver organogenesis promoted by endothelial cells prior to vascular function. Science,? 2001,294(5542):559-563.
16.	Lammert E, Cleaver O, Melton D. Induction of pancreatic differentiation by signals from blood vessels. Science, 2001,294(5542):564-567.

1. 　Orlic D, Kajstura J, Chimenti S, et al.Bone marrow cells regenerate infarcted myocardium. Nature, 2001, 410 (6829) :701-705.
2. 　朱洪生,黄日太,连锋,等.骨髓间质干细胞移植对香猪急性心肌梗死后心肌结构和心功能的影响.中国胸心血管外科临床杂志,2004,11(2):112-115.
3. 　连锋,朱洪生,薛松,等. 自体内皮祖细胞移植对急性心肌梗死近、中期心肌收缩力的影响. 中国胸心血管外科临床杂志,2006,13(5):326-330.
4. 　Agbulut O, Menot ML, Li Z, et al. Temporal patterns of bone marrow cell differentiation following transplantation in doxorubicin-induced cardiomyopathy. Cardiovasc Res,2003, 58(2):451-459.
5. 　Behfar A,Terzic A. Derivation of a cardiopoietic population from human mesenchymal stem cells yields cardiac progeny. Nat Clin Pract Cardiovasc Med,2006,3(Suppl 1):S78-S82.
6. 　Briguori C, Reimers B, Sarais C, et al. Direct intramyocardial percutaneous delivery of autologous bone marrow in patients with refractory myocardial angina. Am Heart J, 2006,151(3):674-680.
7. 　Bittira B, Kuang JQ, Al-Khaldi A, et al. In vitro preprogramming of marrow stromal cells for myocardial regeneration. Ann Thorac Surg, 2002,74(4):1154-1159.
8. 　Rangappa S, Entwistle J, Wechsler AS, et al. Cardiomyocyte-mediated contact programs human mesenchymal stem cells to express cardiogenic phenotype. J Thorac Cardiovasc Surg,2003, 126(1):124-132.
9. 　Shake JG, Gruber PJ, Baumgartner WA, et al. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg, 2002, 73(6):1919-1925.
10. 　Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation, 2002, 106(15):1913-1918.
11. 　Assmus B, Schchinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation, 2002, 106(24):3009-3017.
12. 　Wang JS, Shun-Tim D, Galipeau J, et al. Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages. J Thorac Cardiovasc Surg, 2000, 120(5):999-1005.
13. 　Zhang S, Wang D, Estrov Z, et al. Both cell fusion and transdifferentiation account for the transformation of human peripheral blood CD34-positive cells into cardiomyocytes in vivo. Circulation, 2004,110(25):3803-3807.
14. 　Anderson DJ, Gage FH, Weissman IL.Can stem cells cross lineage boundaries? Nat Med, 2001, 7(4):393-395.
15. 　Matsumoto K, Yoshitomi H, Rossant J, et al. Liver organogenesis promoted by endothelial cells prior to vascular function. Science,? 2001,294(5542):559-563.
16. 　Lammert E, Cleaver O, Melton D. Induction of pancreatic differentiation by signals from blood vessels. Science, 2001,294(5542):564-567.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Dose-Dependent Relationship of Bone Marrow Mesenchymal Stem Cells Transplantation to Cardiomyogenesis for Functional Regenerative Recovery after Myocardial Infarction

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