Unfathomed Nanomessages to the Heart: Translational Implications of Stem Cell-Derived, Progenitor Cell Exosomes in Cardiac Repair and Regeneration

Abstract

Exosomes formed from the endosomal membranes at the lipid microdomains of multivesicular bodies (MVBs) have become crucial structures responsible for cell communication. This paracrine communication system between a myriad of cell types is essential for maintaining homeostasis and influencing various biological functions in immune, vasculogenic, and regenerative cell types in multiple organs in the body, including, but not limited to, cardiac cells and tissues. Characteristically, exosomes are identifiable by common proteins that participate in their biogenesis; however, many different proteins, mRNA, miRNAs, and lipids, have been identified that mediate intercellular communication and elicit multiple functions in other target cells. Although our understanding of exosomes is still limited, the last decade has seen a steep surge in translational studies involving the treatment of cardiovascular diseases with cell-free exosome fractions from cardiomyocytes (CMs), cardiosphere-derived cells (CDCs), endothelial cells (ECs), mesenchymal stromal cells (MSCs), or their combinations. However, most primary cells are difficult to culture in vitro and to generate sufficient exosomes to treat cardiac ischemia or promote cardiac regeneration effectively. Pluripotent stem cells (PSCs) offer the possibility of an unlimited supply of either committed or terminally differentiated cells and their exosomes for treating cardiovascular diseases (CVDs). This review discusses the promising prospects of treating CVDs using exosomes from cardiac progenitor cells (CPCs), endothelial progenitor cells (EPCs), MSCs, and cardiac fibroblasts derived from PSCs.

Keywords: cardiac repair; cardiovascular disease; exosomes; progenitor cells; stem cells.

Figure 1

Generation of differential exosomes from various progenitor cells of the mesoderm lineage, derived from a common mesangioblast differentiated from PSCs for treating CVDs: PSCs can be cued to differentiate into the mesodermal lineage to form mesangioblasts expressing VEGFR2 and CD56. PSC-derived mesangioblasts could be further differentiated into Isl-1-expressing CPCs, MSCs expressing CD90, CD105, and CD73, CD31⁺ and Sca-1+ EPCs, and αSMA⁺ SMCs in vitro. These progenitor cells could be culture expanded on a large scale, and their exosomes can be collected. Therapeutic use of these exosomes in combination is likely to impart synergistic improvement in cardiomyocyte survival, the reduction of inflammation, and the induction of angiogenesis.