Myocardial infarction (MI), a leading cause of death worldwide, can cause irreversible damages to the myocardium. Given the limited regenerative capacity of the human heart following myocardial injury, stem cell-based therapies have emerged as a promising therapeutic approach for improving cardiac regeneration and function. One such stem cell, the human hematopoietic CD34+ stem cell, has proven to be extremely beneficial; in early phase clinical trials and in laboratory experiments it has been shown to improve cardiac function and induce vascular angiogenesis in the ischemic myocardium. Involvement of cell-secreted paracrine factors in the angiogenic process has been suspected; however, the precise mechanisms by which these paracrine factors induce angiogenesis and therapeutic recovery are poorly understood. Earlier, our group has demonstrated for the first time that human CD34+ cells actively secrete membrane-bound nano-vesicles called exosomes that constitute a significant proangiogenic component of its paracrine secretion. Further, recently submitted data and preliminary data from my laboratory indicate that the isolated cell-free exosomes has similar therapeutic activity as the CD34+ cells, independent of the cells themselves. We have also identified that CD34+ exosomes could carry and transfer several proangiogenic microRNAs, such as miR-126 to target endothelial cells. Therefore, we hypothesize that the beneficial angiogenesis associated with CD34+ cell-therapy for myocardial repair is primarily mediated by the direct transfer of pro-angiogenic miRNAs from CD34+ cells via exosomes, and that increasing the pro-angiogenic miRNA content of CD34+ exosomes would augment the efficacy of ischemic tissue repair of CD34+ exosomes. We propose to characterize the molecular content and mechanisms of CD34+ exosomes that are responsible for its angiogenic and therapeutic function in a mouse model of myocardial infarction (MI) with the following specific aims: 1. Determine the therapeutic efficacy of CD34+ exosomes and study the role of CD34+ exosomes-derived miR-126 in cardiac angiogenesis and functional recovery after MI; 2. Characterize the molecular mechanisms of CD34+ exosomes-induced angiogenesis; 3. Improve the regenerative efficacy of CD34+ exosomes. Our study will be the first one to examine the molecular composition and function of exosomes from the paracrine secretion of human stem cells that can shuttle genetic material such as microRNAs to target cells. Our studies will positively impact cardiovascular regenerative medicine in at least 3 ways: 1) by characterizing the predominant, but as yet undefined, paracrine mechanism of CD34+ cell therapy; 2) by discovering previously unknown miRNA-induced mechanisms, which could be a novel tool for drug discovery; and 3) by beginning to determine whether CD34+ exosomes could be a useful, cell-free alternative to CD34+ cell therapy. In addition to performing similar therapeutic functions safely and effectively, direct use of exosomes as a therapeutic entity has the potential to overcome the challenges of cell therapy and to develop alternative cell-free strategies that could lead to customized therapy for chronically ill patients with functionally impaired stem cells.
|Effective start/end date||8/1/14 → 4/30/19|
- National Heart, Lung, and Blood Institute (1R01HL124187-01)