The prospect of a cell based therapy for cellular regeneration and functional recovery of the heart was realized with the discovery that stem cells can contribute to myocyte formation in the adult and that these stem cells may also participate in the repair of the heart after injury. It is now clear the heart has inherent regenerative capacity however it is also clear that this capacity is limited. Transplantation of mesenchymal stem cells into patients evokes a reproducible increase in function and provides insight into the potential of this therapeutic approach. To date, little is known of the systems that create and maintain the inherent cardiac stem cells (CSC) and how they participate in day to day function and homeostasis or during and after injury. Stromal cell derived factor 11 (SDF1), and its receptor, CXCR4 are key components of the biological system that regulates hematopoiesis and hematopoietic stem cells. We have found this SDF1-CXCR4 axis in the heart and both are expressed on myocytes and fibroblasts and are functionally coupled to MAPK and AKT signaling that serves a survival function in vitro and in vivo against ischemia reperfusion injury. Both SDF1 and CXCR4 knockouts are embryonic lethal with cardiac defects. These novel findings serve to provide the basis for our hypothesis, that the cardiac SDF1-CXCR4 axis plays a role in cardiac homeostasis through the action on cardiac stem cells, myocytes, and fibroblasts. Myocyte and fibroblast expression of SDF1 and CXCR4 are proposed to serve a similar function for cardiac stem cell maintenance and protection (niche formation) as stromal and osteoblasts do in the bone marrow. The effectiveness of this system in protecting and maintaining the myocardium with stress or injury is limited due to attenuated SDF1-CXCR4 signaling by desensitization of SDF1-CXCR4 signaling. We propose this effectiveness may be increased by increasing the number of receptors and/or limiting desensitization of SDF1- CXCR4 signaling. The following Aims seek to further define the role of the SDF1-CXCR4 axis in cardiac homeostasis and regeneration and to determine how CSC function in cardiac regeneration can be enhanced through optimization of CXCR4 signaling as a cell based therapy in cardiac injury.
Aim 1 : To determine the role that cardiac SDF1-CXCR4 plays in maintaining cardiac homeostasis in myocyte, myofibroblast, and cardiac stem cells.
Aim 2 : To determine how desensitization/downregulation of SDF1-CXCR4 signaling limits the functionality of cardiac stem cells.
Aim 3 : To determine whether increasing signaling and signaling efficacy through the SDF1-CXCR4 axis in cardiac stem cells facilitates increased regenerative capacity by administration early and late after MI and IR injury.
Aim 4 : To determine whether SDF1-CXCR4 synergizes with HGF-cMET and IGF1-IGFR signaling systems to increase functions critical to stem cell engraftment and repair of functional myocardium. The seminal finding that the heart contains a population of stem cells that can contribute to repair of the injured heart has provided new hope for a cell based therapy for cardiac repair. The research described in this proposal will advance our understanding of and provide mechanistic insight into inherent cardiac systems that regulate the function of cardiac stem cells and their relationship with cardiac muscle and supporting cells. Results from these mechanistic studies will provide the impetus to design novels strategies to overcome inherent limitations of cardiac stem cell participation in cardiac regeneration after cardiac injury or with disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091202-04
Application #
8131612
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Schwartz, Lisa
Project Start
2008-09-01
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2011
Total Cost
$370,000
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Tang, Xian-Liang; Li, Qianhong; Rokosh, Gregg et al. (2016) Long-Term Outcome of Administration of c-kit(POS) Cardiac Progenitor Cells After Acute Myocardial Infarction: Transplanted Cells Do not Become Cardiomyocytes, but Structural and Functional Improvement and Proliferation of Endogenous Cells Persist for at L Circ Res 118:1091-105
Wysoczynski, Marcin; Solanki, Mitesh; Borkowska, Sylwia et al. (2014) Complement component 3 is necessary to preserve myocardium and myocardial function in chronic myocardial infarction. Stem Cells 32:2502-15
Dimova, Neviana; Wysoczynski, Marcin; Rokosh, Gregg (2014) Stromal cell derived factor-1? promotes C-Kit+ cardiac stem/progenitor cell quiescence through casein kinase 1? and GSK3?. Stem Cells 32:487-99
Bolli, Roberto; Tang, Xian-Liang; Sanganalmath, Santosh K et al. (2013) Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Circulation 128:122-31
Sanganalmath, Santosh K; Bolli, Roberto (2013) Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res 113:810-34
Madonna, Rosalinda; Rokosh, Gregg (2012) Insights into gene therapy for critical limb ischemia: the devil is in the details. Vascul Pharmacol 57:10-4
Obal, Detlef; Dai, Shujing; Keith, Rachel et al. (2012) Cardiomyocyte-restricted overexpression of extracellular superoxide dismutase increases nitric oxide bioavailability and reduces infarct size after ischemia/reperfusion. Basic Res Cardiol 107:305
Tang, Xian-Liang; Rokosh, D Gregg; Guo, Yiru et al. (2010) Cardiac progenitor cells and bone marrow-derived very small embryonic-like stem cells for cardiac repair after myocardial infarction. Circ J 74:390-404
Madonna, Rosalinda; Rokosh, Gregg; De Caterina, Raffaele et al. (2010) Hepatocyte growth factor/Met gene transfer in cardiac stem cells--potential for cardiac repair. Basic Res Cardiol 105:443-52
Tang, Xian-Liang; Rokosh, Gregg; Sanganalmath, Santosh K et al. (2010) Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction. Circulation 121:293-305

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