Abstract 549: Characterization of Mesenchymal Stromal Cell-derived Exosomes From Patients With Improved Function Outcome After Ischemic Cardiomyopathy: A Biorepository Evaluation of the Focus-CCTRN Trial

Abstract

Mesenchymal stromal cells derived from bone marrow (BM-MSCs) have been considered promisingcandidates for regenerative medicine therapies for more than 20 years, but to date cardiovascular clinicaltrials of MSC-based therapies have demonstrated only modest improvement. However, the mechanismsunderlying why some patients improve and others do not remain undefined. Although MSC survival aftertransplantation remains a challenge, several studies have reported that BM-MSC-mediated paracrineeffects and delivery of exosomes may be therapeutically relevant. We hypothesized that MSC-derivedexosomes from patients with cardiac functional improvement contain factors that promote cell survival,proliferation, and cardiac protection. Here, we compared exosomes (derived from MSCs that had beenexpanded from BM-MNCs used for autologous transplantation) from two cohorts of disease- and age-matched consented patients with ischemic cardiomyopathy enrolled in the FOCUS-CCTRN trial—thosewith improved (cohort1, n=3) or worsened (cohort2, n=3) functional outcome in three primary endpoints:left ventricular (LV) ejection fraction, LV end-systolic volume, and maximal oxygen consumption.MicroRNA-seq analysis identified 16 upregulated and 12 downregulated miRNAs in cohort 1 whencompared to cohort 2. Using DIANA-Mir Path v.3.0, we identified 3,522 experimentally validated genetargets. Gene set enrichment analysis identified enrichment for fatty acid biosynthesis and metabolism,Hippo signaling pathway, protein processing in endoplasmic reticulum, adherent junction, cell cycle,endocytosis, RNA transport and degradation, estrogen-signaling pathway, regulation of actincytoskeleton, Prolactin signaling pathway, Focal adhesion, Notch-signaling pathway, p53-signalingpathway, insulin-signaling pathway and HIF-1-signaling pathway in the targets of upregulated miRNAs.The downregulated miRNAs were related to extracellular matrix-receptor interaction, protein processingin endoplasmic reticulum, cytokine-cytokine receptor interaction and antigen processing andpresentation. Thus, the identified miRNAs differentially expressed in patients with an improved functionaloutcome that may play a role in the molecular mechanisms that underlie in cardiac repair in patients withischemic cardiac disease. Moreover, these finding indicate that not all autologous cell products may becompetent therapy candidates for cardiac repair These results warrant further investigation to confirmthe effects of the identified differences on the target genes, which could improve the prognosis and unveilnew therapeutic approaches.