Lack of understanding of basic stem cell mechanisms limits current therapeutic approaches. In this renewal application, we will focus on the use of c-kit* cardiac progenitor cells (CPCs) to protect the heart against post-myocardial infarction (Ml) remodeling and heart failure (HF). The overall goal is to elucidate the molecular mechanisms that regulate the properties of CPCs and to evaluate the therapeutic utility of enhancing CPC function in order to optimize cardiac repair. Four closely inter-related and inter-dependent Projects will address different facets of this theme. Project 1 (Belli) will elucidate the role of CO and NO in regulating CPC function and therapeutic efficacy. The central hypothesis is that these gases are kev determinants of CPC competence and that augmenting their levels will dramatically enhance CPC-mediated cardiac repair. Project 2 (Prabhu) will illuminate the deleterious effects of TNF on CPC competence and reparative ability. This project will test the hypothesis that differential TNF signaling via TNFR1, TNFR2, and NF-KB plavs a critical role in determining adrenergic versus cardiomyogenic fate and, consequently, the reparative capacity of CPCs following Ml. Project 3 (Jones) will examine the role of protein 0-GlcNAcylation in modulating the fundamental properties of CPCs and will test the hypothesis that the 0-GlcNAc alarm signal plays a critical role in regulating CPC proliferation, survival, differentiation, and paracrine function. Project 4 (Bhatnagar) will determine how diabetes affects CPC-mediated myocardial repair and how CPC therapy can be optimized for the diabetic heart. The central hypothesis is that diabetes undermines CPC competence by inducing insulin resistance. Thus, all four Projects focus cohesively on CPCs. These Projects will be supported by four Cores that will provide expertise in mouse surgery, cell transplantation, CPC culture and phenotyping, pathology, flow cytometry, and cell sorting. This highly-focused PPG will be led by investigators who have collaborated productively for many years. Their long history of collaboration has resulted in closely integrated Projects that are ideally suited for a PPG. These will be the first studies to examine the role of CO and NO, TNF, 0-GlcNAcylation, and type 2 diabetes on CPC function: consequently, the results will be entirely new and will advance our understanding of CPC biology. In addition, these studies may lay the groundwork for new translational investigations of CPC therapy in patients with HF. Since we have already initiated the first-in-humans clinical trial of unmodified CPCs in patients with HF, we are well positioned to rapidly translate any insights derived from this Program into new clinical investigations.
In 2009, we started SCIPIO, the first-in-humans study of c-kit+ cardiac progenitor cells (CPCs). The initial results are encouraging. This Program builds on SCIPIO and seeks to optimize the effectiveness of these promising CPCs therapies. If our hypotheses are confirmed, the results will lead to the use of more efficacious cell therapies in patients with heart failure. Since we have developed the infrastructure to launch new clinical studies of CPCs, any new insights gained in this Program will be rapidly translated.
|Khan, Abdur Rahman; Farid, Talha A; Pathan, Asif et al. (2016) Impact of Cell Therapy on Myocardial Perfusion and Cardiovascular Outcomes in Patients With Angina Refractory to Medical Therapy: A Systematic Review and Meta-Analysis. Circ Res 118:984-93|
|Salabei, Joshua K; Lorkiewicz, Pawel K; Mehra, Parul et al. (2016) Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells. J Biol Chem 291:13634-48|
|Tokita, Yukichi; Tang, Xian-Liang; Li, Qianhong et al. (2016) Repeated Administrations of Cardiac Progenitor Cells Are Markedly More Effective Than a Single Administration: A New Paradigm in Cell Therapy. Circ Res 119:635-51|
|Moore 4th, Joseph B; Zhao, John; Keith, Matthew C L et al. (2016) The Epigenetic Regulator HDAC1 Modulates Transcription of a Core Cardiogenic Program in Human Cardiac Mesenchymal Stromal Cells Through a p53-Dependent Mechanism. Stem Cells 34:2916-2929|
|Hamid, Tariq; Xu, Yuanyuan; Ismahil, Mohamed Ameen et al. (2016) TNF receptor signaling inhibits cardiomyogenic differentiation of cardiac stem cells and promotes a neuroadrenergic-like fate. Am J Physiol Heart Circ Physiol 311:H1189-H1201|
|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|
|Conklin, Daniel J; Guo, Yiru; Jagatheesan, Ganapathy et al. (2015) Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury. Circ Res 117:437-49|
|Wysoczynski, Marcin; Ratajczak, Janina; Pedziwiatr, Daniel et al. (2015) Identification of heme oxygenase 1 (HO-1) as a novel negative regulator of mobilization of hematopoietic stem/progenitor cells. Stem Cell Rev 11:110-8|
|Salabei, Joshua K; Hill, Bradford G (2015) Autophagic regulation of smooth muscle cell biology. Redox Biol 4:97-103|
|Tang, Xian-Liang; Rokosh, Gregg; Sanganalmath, Santosh K et al. (2015) Effects of Intracoronary Infusion of Escalating Doses of Cardiac Stem Cells in Rats With Acute Myocardial Infarction. Circ Heart Fail 8:757-65|
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