Circulation Research. 2006;98:1414-1421
Published online before print May 11, 2006, doi: 10.1161/01.RES.0000225952.61196.39
Published online before print May 11, 2006, doi: 10.1161/01.RES.0000225952.61196.39
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© 2006 American Heart Association, Inc.
Integrative Physiology |
Bone Marrow Stem Cells Prevent Left Ventricular Remodeling of Ischemic Heart Through Paracrine Signaling
From the Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Ohio.
Correspondence to Muhammad Ashraf, PhD, Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267-0529. E-mail muhammad.ashraf{at}uc.edu
In this study, we hypothesized that bone marrow stem cells (BMSCs) protect ischemic myocardium through paracrine effects that can be further augmented with preconditioning. In in vitro experiments, cell survival factors such as Akt and eNOS were significantly increased in BMSCs following anoxia. In the second series of experiments following coronary ligation in mice, left ventricles were randomly injected with the following: DMEM (G-1), BMSCs (G-2), and preconditioned BMSCs (G-3). Four days after myocardial infarction, BMSCs were observed within injured myocardium in G-2 and G-3. Apoptotic cardiomyocytes within periinfarct area were significantly reduced in G-3. Four weeks after myocardial infarction, smaller left ventricular (LV) dimension and increased LV ejection fraction were observed in G-3. Infarct area was significantly reduced in G-3. However, GFP+ cardiomyocytes were observed in low numbers within periinfarct area in G-2 and G-3. In conclusion, BMSCs secreted cell survival factors under ischemia, and they prevented apoptosis in cardiomyocytes adjacent to the infarcted area. Preconditioning of BMSCs enhanced their survival and ability to attenuate LV remodeling, which was attributable, in part, to paracrine effects.
Key Words: stem cells • paracrine effect • preconditioning • ischemia • remodeling
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 |
|
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|
|
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|
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 |
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|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
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|
|
|
|
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|
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|
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|
|
|
|
|
|
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|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 S. Dimmeler, J. Burchfield, and A. M. Zeiher Cell-Based Therapy of Myocardial Infarction Arterioscler Thromb Vasc Biol, February 1, 2008; 28(2): 208 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Shujia, H. K. Haider, N. M. Idris, G. Lu, and M. Ashraf Stable therapeutic effects of mesenchymal stem cell-based multiple gene delivery for cardiac repair Cardiovasc Res, February 1, 2008; 77(3): 525 - 533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Pasha, Y. Wang, R. Sheikh, D. Zhang, T. Zhao, and M. Ashraf Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium Cardiovasc Res, January 1, 2008; 77(1): 134 - 142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 T. A. Markel, P. R. Crisostomo, M. Wang, C. M. Herring, and D. R. Meldrum Activation of individual tumor necrosis factor receptors differentially affects stem cell growth factor and cytokine production Am J Physiol Gastrointest Liver Physiol, October 1, 2007; 293(4): G657 - G662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Wang, W. Zhang, P. Crisostomo, T. Markel, K. K. Meldrum, X. Y. Fu, and D. R. Meldrum Sex differences in endothelial STAT3 mediate sex differences in myocardial inflammation Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E872 - E877. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E.M. Winter, R.W. Grauss, B. Hogers, J. van Tuyn, R. van der Geest, H. Lie-Venema, R. V. Steijn, S. Maas, M.C. DeRuiter, A.A.F. deVries, et al. Preservation of Left Ventricular Function and Attenuation of Remodeling After Transplantation of Human Epicardium-Derived Cells Into the Infarcted Mouse Heart Circulation, August 21, 2007; 116(8): 917 - 927. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Singla, G. E. Lyons, and T. J. Kamp Transplanted embryonic stem cells following mouse myocardial infarction inhibit apoptosis and cardiac remodeling Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1308 - H1314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. H. Wu, B. Zhou, C. T. Yu, B. Cui, S. H. Lu, Z. C. Han, and Y. L. Liu Therapeutic Potential of Human Umbilical Cord Derived Stem Cells in a Rat Myocardial Infarction Model Ann. Thorac. Surg., April 1, 2007; 83(4): 1491 - 1498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Abraham and G. Gerstenblith Preconditioning Stem Cells for Cardiovascular Disease: An Important Step Forward Circ. Res., March 2, 2007; 100(4): 447 - 449. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 K. H. Wu, Y. L. Liu, B. Zhou, and Z. C. Han Cellular therapy and myocardial tissue engineering: the role of adult stem and progenitor cells Eur. J. Cardiothorac. Surg., November 1, 2006; 30(5): 770 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|