Cardiac regeneration with bone marrow derived stem cells (BMSCs) is a novel approach to repair the infarcted myocardium. Unfortunately, stem cell homing to the infarcted myocardium and proliferation are very inefficient, leading to only limited differentiation into cardiac myocytes. This approach is, therefore, not fully effective for recovery of heart function. Once stem cells reach the infarcted myocardium, they are exposed to an ischemic environment in which their survival is in jeopardy. The stage of infarction is an important consideration as scar tissue forms when the infarction is advanced. Our preliminary data show that CXCR4 overexpressing MSCs (CXCR4+-MSCs) are an optimal subpopulation of BMSCs that are attracted to the infarcted myocardium and contribute to increased angiomyogenesis. Moreover, CXCR4+-MSCs secrete anti- fibrotic factors and survival proteins, which mediate enhanced engraftment and proliferation. Our preliminary data support the hypothesis that newly formed cardiomyocytes derived from CXCR4+-MSCs can proliferate profusely upon pharmacological interventions and possibly expedite the process of repopulating the infarcted myocardium.The following hypotheses will be tested. Hypothesis 1: CXCR4+-MSCs repair the infarcted myocardium by releasing anti-fibrotic factors and survival proteins.
In Aim 1 we will test the sub-hypotheses that: 1A, Overexpression of CXCR4+ results in enhanced MSC survival and engraftment in the infarcted myocardium;1B, CXCR4+-MSCs attenuate remodeling post-myocardial infarction by releasing anti-fibrotic enzymes;and 1C, CXCR4+-MSCs reduce ischemic injury by upregulation of Akt. Hypothesis 2: CXCR4+ expression on MSCs promotes their angiomyogenic potential.
In Aim 2 we will test the sub-hypotheses that: 2A, CXCR4+-MSCs promote angiogenesis by releasing angiogenic factors;2B, CXCR4+-MSCs express cytoprotective or survival proteins which enhance their myogenic potential in the infarcted myocardium. Hypothesis 3: Regeneration of infarcted myocardium is maximized by disintegration of scar tissue and proliferation of newly formed myocytes.
In Aim 3 we will test the hypotheses that: 3A, Cardiac scar formation in the infarcted area retards the engraftment of MSCs;3B, In response to a potent cell cycle reentry stimulant, enhanced myogenesis from CXCR4+-MSCs leads to repopulation of the infarcted area. These therapeutic approaches have the potential to be developed into therapies for human myocardial infarction.

Public Health Relevance

CXCR4 stem cells are an optimal subtype of BMSC for cardiac repair;the anti-fibrotic effects of CXCR4+- MSCs and use of potent cell cycle reentry stimulants are novel and innovative. It is expected that effective engraftment and proliferation of CXCR4+-MSCs in ischemic tissue will profusely populate the infarcted area, improving cardiac function, and that knowledge gained from this work will lead to new strategies to treat the myocardial infarction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089824-02
Application #
7662581
Study Section
Special Emphasis Panel (ZRG1-CVS-D (02))
Program Officer
Adhikari, Bishow B
Project Start
2008-08-01
Project End
2013-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$390,000
Indirect Cost
Name
University of Cincinnati
Department
Pathology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Cai, Wen-Feng; Kang, Kai; Huang, Wei et al. (2015) CXCR4 attenuates cardiomyocytes mitochondrial dysfunction to resist ischaemia-reperfusion injury. J Cell Mol Med 19:1825-35
Wang, Yuhua; Huang, Wei; Liang, Jialiang et al. (2014) Suicide gene-mediated sequencing ablation revealed the potential therapeutic mechanism of induced pluripotent stem cell-derived cardiovascular cell patch post-myocardial infarction. Antioxid Redox Signal 21:2177-91
Huang, Wei; Dai, Bo; Wen, Zhili et al. (2013) Molecular strategy to reduce in vivo collagen barrier promotes entry of NCX1 positive inducible pluripotent stem cells (iPSC(NCX¹?)) into ischemic (or injured) myocardium. PLoS One 8:e70023
Feng, Yuliang; Wang, Yuhua; Cao, Nan et al. (2012) Progenitor/stem cell transplantation for repair of myocardial infarction: Hype or hope? Ann Palliat Med 1:65-77
Liang, Jialiang; Huang, Wei; Yu, Xiyong et al. (2012) Suicide gene reveals the myocardial neovascularization role of mesenchymal stem cells overexpressing CXCR4 (MSC(CXCR4)). PLoS One 7:e46158
Huang, Wei; Wang, Tao; Zhang, Dongsheng et al. (2012) Mesenchymal stem cells overexpressing CXCR4 attenuate remodeling of postmyocardial infarction by releasing matrix metalloproteinase-9. Stem Cells Dev 21:778-89
Dai, Bo; Huang, Wei; Xu, Meifeng et al. (2011) Reduced collagen deposition in infarcted myocardium facilitates induced pluripotent stem cell engraftment and angiomyogenesis for improvement of left ventricular function. J Am Coll Cardiol 58:2118-27
Huang, Wei; Zhang, Dongsheng; Millard, Ronald W et al. (2010) Gene manipulated peritoneal cell patch repairs infarcted myocardium. J Mol Cell Cardiol 48:702-12
Zhang, Xiaowei; Wang, Xiaohong; Zhu, Hongyan et al. (2010) Synergistic effects of the GATA-4-mediated miR-144/451 cluster in protection against simulated ischemia/reperfusion-induced cardiomyocyte death. J Mol Cell Cardiol 49:841-50
Wang, Yigang; Zhang, Dongsheng; Ashraf, Muhammad et al. (2010) Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction. Am J Physiol Heart Circ Physiol 298:H275-86

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