Available evidence from pre-clinical and clinical studies indicates that adult autologous stem cell based therapies show modest improvement of cardiac function. Emerging evidence from preclinical studies also suggests that hostile micro-environment in the infarcted myocardium, including inflammation and oxidative damage, have adverse effects on transplanted stem cell survival and function thereby posing a significant barrier to the adult stem cell-based therapies for repair of injured myocardium. Therefore, novel approaches to enhance full functional benefits of stem cell based therapies are critically needed. Pluripotent Stem cells including induced pluripotent stem cells (iPS) and embryonic stem cells (ESCs) have provided an alternative for the resurrection of damaged myocardium yet their use remains technically challenging and risky and cellular derivatives of pluripotent cells may still face the similar challenges of low engraftment and survival as is noted with adult stem cells. Therefore use of cell-free components derived from stem cells including iPS and ES cells, need to be explored for their reparative potential. Exosomes derived from such cells may provide one such cell-free source. Exosomes, known regulators of intercellular communication, carry the cell specific mRNA/miRNA signature and participate in cell-cell communication by transferring their materials to the target cells. Our preliminary data indicates that, ESC derived exosomes represent a novel cell free system capable of supporting myocardial regeneration, in part, by inducing cardiomyocyte proliferation and by enhancing cardiac progenitor cell augmentation, proliferation and differentiation. Therefore we hypothesize that ES/iPS-derived exosomes may represent a novel strategy to augment endogenous repair processes in the infarcted myocardium. Our goal is to establish that pluripotent stem cell-derived exosomes as a novel cell free therapeutic regimen for myocardial repair in response to chronic pathological insult. The significance of this study is to develop a novel understanding of the role played by mES cell derived exosomes in supporting cardiomyocyte and cardiac progenitor cells (CPCs) based reparative processes in the heart. We will also extend these studies to determine the contribution of pluripotent cell specific miRNAs in regulating CPC reparative response to pathologic injury. Establishing the therapeutic value of these exosomes would help develop a novel cell free system to enhance myocardial repair and would provide a new direction for the restoration and/or augmentation of endogenous myocardial repair process.
Heart disease is a leading cause of morbidity and mortality amongst Americans. Adult stem cells including autologous cardiac progenitor cells (CPC) are currently used in the clinical trials to enhance the repair and regeneration of the diseased heart and have shown significant improvement in patients with ischemic heart disease. The available results however show modest gain in improved heart functions in patients treated with stem cells. Part of the reasons that limit the full benefits of such therapies is poor survival of transplanted cells and inefficient activation of tissue residing stem cells. Studies proposed in ths application provide a novel approach to enhance the survival and function of CPC. Most importantly, our results may significantly improve the benefits of an existing cellular therapy and improve the lives of the over 16 million patients in the United States living with coronary heart disease.
Showing the most recent 10 out of 24 publications
