Circulating exosomes derived from transplanted progenitor cells aid the functional recovery of ischemic myocardium

Abstract

The stem cell field is hindered by its inability to noninvasively monitor transplanted cells within the target organ in a repeatable, time-sensitive, and condition-specific manner. We hypothesized that quantifying and characterizing transplanted cell–derived exosomes in the recipient plasma would enable reliable, noninvasive surveillance of the conditional activity of the transplanted cells. To test this hypothesis, we used a human-into-rat xenogeneic myocardial infarction model comparing two well-studied progenitor cell types: cardiosphere-derived cells (CDCs) and c-kit+ cardiac progenitor cells (CPCs), both derived from the right atrial appendage of adults undergoing cardiopulmonary bypass. CPCs outperformed the CDCs in cell-based and in vivo regenerative assays. To noninvasively monitor the activity of transplanted CDCs or CPCs in vivo, we purified progenitor cell–specific exosomes from recipient total plasma exosomes. Seven days after transplantation, the concentration of plasma CPC-specific exosomes increased about twofold compared to CDC-specific exosomes. Computational pathway analysis failed to link CPC or CDC cellular messenger RNA (mRNA) with observed myocardial recovery, although recovery was linked to the microRNA (miRNA) cargo of CPC exosomes purified from recipient plasma. We further identified mechanistic pathways governing specific outcomes related to myocardial recovery associated with transplanted CPCs. Collectively, these findings 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 cells. These data implicate the surveillance potential of cell-specific exosomes for allogeneic cell therapies.

Ticagrelor Enhances Release of Anti-Hypoxic Cardiac Progenitor Cell-Derived Exosomes Through Increasing Cell Proliferation In Vitro

“…Our results are in line with previous study showing that intracellular enrichment of HSP70 inhibits the expression of HIF1α by protecting hypoxic cells 59 . Indeed, hCPCs-derived exosomes are effectively internalized by cardiomyocytes [21][22][23]26 .…”

“…Although pro-survival effects of HSP70 are supported by the present results and by others 56 , we cannot exclude that other proteins may synergize the anti-hypoxic effects of ticagrelor-induced exosomes. Despite our limited understanding of cardiac-derived mesenchymal progenitor cells function in vivo in terms of cardiac regeneration, these cells reside in human heart 23,26 and may be a potential target of ticagrelor in mediating exosome-based cardiomyocyte protection. However, further experiments should be performed in an in vivo setting in order to confirm our in vitro results supporting wide evidence of ticagrelor-induced cardioprotection.…”

Circulating Donor Heart Exosome Profiling Enables Noninvasive Detection of Antibody-mediated Rejection

“…In animal transplantation models, we found this to be the case that transplant exosome profiles enabled noninvasive diagnosis of rejection, before histologic evidence of injury to the graft. 11 - 13 …”

“…Exosomes were isolated from thawed plasma sample by size exclusion chromatography along with ultracentrifugation. 12 , 13 Exosomes were analyzed on the NanoSight NS300 nanoparticle detector on the light scatter mode for quantification and size distribution according to manufacturer’s protocols (Malvern Instruments Inc., Westborough, MA). Cryo-electron microscopy analysis of extracellular vesicles was performed at the University of Pennsylvania core facility using the standard protocol.…”

“… 8 - 10 In the context of transplantation, we demonstrated that circulating transplant tissue-specific exosome profiles might serve as a noninvasive biomarker of acute rejection. 11 - 13 In a rodent allogeneic heart transplantation model, donor heart exosome profiles predicted early acute rejection with 100% accuracy, 11 before histologic evidence of grade 1R rejection. Given these findings, we embarked on a pilot study in 4 heart transplant recipients in the perioperative period to investigate whether transplant heart exosomes can be reliably profiled from recipient blood in the clinical setting.…”