Animal and preliminary human studies of adult stem cell therapy, including therapies with endothelial progenitor cells (EPC), for myocardial repair have shown an overall improvement of cardiac function. However, repair of dead or injured myocardium and improvement of cardiac function remains a serious challenge. Emerging evidence from preclinical studies suggests that hostile micro-environment in the infarcted myocardium, including inflammation and oxidative damage, have adverse effects on stem cell survival and function. We have earlier demonstrated that interleukin-10 (IL-10) therapy greatly limits the remodeling in the infarcted myocardium of mice and significantly improves post-infarct cardiac function. Whether IL10 directly alters the biology of EPCs leading to their greater survival and function is not known and warrants an inquiry. The premise of our proposed research is based on our following published and preliminary observations that IL10 therapy: a) attenuates post-MI LV dysfunctions and remodeling, b) enhances the retention and survival of intra-myocardially transplanted EPCs in the ischemic myocardium; c) EPCs from IL-10 knockout mice are defective in number of functional properties, d) enhances neo-vascularization in the border zone of infarcted myocardium by enhancing STAT3-dependent expression of VEGF e) increases EPC-mediated neovascularization in the injured myocardial f) increases VEGF expression in EPC through STAT3, g) enhances ischemia-induced EPC mobilization from bone marrow and h) IL-10 regulates EPC function partly by inhibiting miR 375.These data provide convincing evidence that use of IL- 10 in EPC-and other stem cell based therapies may offer significant advantages, both by attenuating adverse myocardial inflammation and by enhancing survival and function of transplanted stem cells. Our central hypothesis is that IL-10 and the activation of its downstream signal transduction pathways, especially STAT3 activation, enhances mobilization, survival, retention and functional properties of EPCs. The experiments described in the current proposal are designed to extend these findings by testing a series of hypotheses grouped according to the following 3 specific aims: 1) Determine the role of IL-10 on EPC biology and function, 2) Elucidate the molecular and signaling mechanisms of IL-10-mediated EPC biology and function; and 3) Determine the role of IL-10 regulated miR-375 in EPC-mediated myocardial repair.

Public Health Relevance

Certain diseases like myocardial infarction (MI) are the major cause of mortality in humans. IL-10 is a known cardio-protective cytokine that reduces inflammatory response and increases new blood vessel formation in the heart after injury. Interestingly, injured heart recruits bone-marrow derived endothelial progenitor/stem cells (EPC) for repair. However, it is not known how IL-10 enhances the benefits provided by progenitor cells in the injured heart. This proposal will test mechanisms by which IL-10 protects EPC against injured tissue hostile microenvironment in which these cells are injected and study its interaction with other signaling molecules in EPC that may affect their survival, biology and function during experimental heart injury. Since EPCs are currently used in clinical trials of patients with heart diseases and since poor survival of EPC in injured heart is significant barrier to the full benefits to stem cell based therapies, data obtained from proposed studies may potentially be crucial in overcoming these limitations and may directly enhanced the efficacy of EPC-based therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091983-08
Application #
9261586
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2009-05-01
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2019-04-30
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Sluijter, Joost Petrus Gerardus; Davidson, Sean Michael; Boulanger, Chantal M et al. (2018) Extracellular vesicles in diagnostics and therapy of the ischaemic heart: Position Paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 114:19-34
Garikipati, Venkata Naga Srikanth; Kishore, Raj (2018) Induced Pluripotent Stem Cells Derived Extracellular Vesicles: A Potential Therapy for Cardiac Repair. Circ Res 122:197-198
Cheng, Zhongjian; Shen, Xinggui; Jiang, Xiaohua et al. (2018) Hyperhomocysteinemia potentiates diabetes-impaired EDHF-induced vascular relaxation: Role of insufficient hydrogen sulfide. Redox Biol 16:215-225
Gupta, Rajesh; Mackie, Alexander R; Misener, Sol et al. (2018) Endothelial smoothened-dependent hedgehog signaling is not required for sonic hedgehog induced angiogenesis or ischemic tissue repair. Lab Invest 98:682-691
Cheng, Zhongjian; Verma, Suresh K; Losordo, Douglas W et al. (2017) Reprogrammed Human Endothelial Cells: A Novel Cell Source for Regenerative Vascular Medicine. Circ Res 120:756-758
Sasi, Sharath P; Yan, Xinhua; Zuriaga-Herrero, Marian et al. (2017) Different Sequences of Fractionated Low-Dose Proton and Single Iron-Radiation-Induced Divergent Biological Responses in the Heart. Radiat Res 188:191-203
Srikanth Garikipati, Venkata Naga; Kishore, Raj (2017) Young Hearts Run Free: Therapeutic Potential of Neonatal Human Cardiac Progenitor Cells Secretome. Circ Res 120:751-752
Verma, Suresh Kumar; Garikipati, Venkata Naga Srikanth; Kishore, Raj (2017) Mitochondrial dysfunction and its impact on diabetic heart. Biochim Biophys Acta Mol Basis Dis 1863:1098-1105
Verma, Suresh K; Garikipati, Venkata N S; Krishnamurthy, Prasanna et al. (2017) Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell-Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium. Circulation 136:940-953
Yue, Yujia; Garikipati, Venkata Naga Srikanth; Verma, Suresh Kumar et al. (2017) Interleukin-10 Deficiency Impairs Reparative Properties of Bone Marrow-Derived Endothelial Progenitor Cell Exosomes. Tissue Eng Part A 23:1241-1250

Showing the most recent 10 out of 48 publications