Using our unique resource of human neonatal cardiac tissue and funded through our previous R01, we have consistently demonstrated that neonatal CPCs (nCPCs) have superior efficacy in repairing the injured heart compared to any other cell type due to a more potent secretome controlled partly by the heat shock factor 1 (HSF1). Critical to the nCPC’s clinical success will be determining their mechanism of myocardial recovery. We have recently reported a head to head comparison between aCDCs and aCPCs that demonstrated that aCPCs outperformed the aCDCs in cell-based and in vivo regenerative assays. To noninvasively monitor the activity of the transplanted aCPCs or aCDCs in vivo, we purified and interrogated progenitor-specific exosomes (EXOs) from the recipient total plasma EXOs. By using our previously published computational modeling which takes advantage of principal component analysis (PCA) and partial least squares regression analysis (PLSR), we identified potentially impactful miRNA signatures within aCPCs–derived circulating EXOs that drives mechanisms of repair in the injured myocardium involving at least two important processes: antifibrosis and increased angiogenesis. For these reasons, we believe that miRNA profiling of transplanted progenitor cell– derived EXOs isolated from recipient plasma more accurately predicts the clinical outcomes seen with stem cell therapy than the RNA profiles of cultured progenitor cells or their EXOs. However, the direct role of the identified miRNAs within transplanted CPCs have not yet been determined in vivo, how the plasma miRNAs change during the post-operative period after cell transplantation, and finally the validity of this methodology and computational modeling in a large preclinical animal model. Thus, we hypothesize that the plasma EXOs reflects specific molecular pathways triggered by the parent transplanted progenitor cells that recovers the injured myocardium. Aim1 will validate whether angiogenesis and antifibrosis mIRs predicted by computational modeling for CPCs are essential for recovering the ischemic myocardium. Aim 2 will determine how the circulating EXOs mIR composition changes post-operatively by computational modeling. Aim3 will expand the predictive capacity of our computational model using transplanted nCPCs in a large animal preclinical porcine MI model. Successful completion will demonstrate that the use of progenitor cells derived from neonatal tissue has the highest regenerative abilities which maybe critical for the clinical success. In addition, we will determine a new paradigm for a more quantitative methodology for cell based therapies to reveal a noninvasive window into the conditional state of the transplanted cells. Collectively, these findings will demonstrate the potential of circulating progenitor cell–specific exosomes as a liquid biopsy that provides a noninvasive window into the conditional state of the transplanted neonatal CPCs. These data implicate the surveillan...