Impaired therapeutic efficacy of bone marrow cells from post-myocardial infarction patients in the TIME and LateTIME clinical trials

Abstract

Implantation of bone marrow-derived cells (BMCs) into mouse hearts post-myocardial infarction (MI) limits cardiac functional decline. However, clinical trials of post-MI BMC therapy have yielded conflicting results. While most laboratory experiments use healthy BMC donor mice, clinical trials use post-MI autologous BMCs. Post-MI mouse BMCs are therapeutically impaired, due to inflammatory changes in BMC composition. Thus, therapeutic efficacy of the BMCs progressively worsens after MI but recovers as donor inflammatory response resolves. The availability of post-MI patient BM mononuclear cells (MNCs) from the TIME and LateTIME clinical trials enabled us to test if human post-MI MNCs undergo a similar period of impaired efficacy. We hypothesized that MNCs from TIME trial patients would be less therapeutic than healthy human donor MNCs when implanted into post-MI mouse hearts, and that therapeutic properties would be restored in MNCs from LateTIME trial patients. Post-MI SCID mice received MNCs from healthy donors, TIME patients, or LateTIME patients. Cardiac function improved considerably in the healthy donor group, but neither the TIME nor LateTIME group showed therapeutic effect. Conclusion: post-MI human MNCs lack therapeutic benefits possessed by healthy MNCs, which may partially explain why BMC clinical trials have been less successful than mouse studies.

Cell-Based HIF1α Gene Therapy Reduces Myocardial Scar and Enhances Angiopoietic Proteome, Transcriptomic and miRNA Expression in Experimental Chronic Left Ventricular Dysfunction

“…Despite safety and feasibility of BM-MNCs transplantation, a comprehensive meta-analysis of intracoronary administered BM-MNCs in patients with acute myocardial infarction (AMI) failed to show a clinically relevant efficacy ( Gyongyosi et al, 2015 ). Reasons for the lack of clinically significant therapeutic effect of BM-MNCs are 1) they comprise of a heterogenous population of mature cells with limited proliferation capacity, 2) BM-MNCs lack a sufficient population of stem cells with regenerative capacity ( Sugihara et al, 2007 ; Wang et al, 2020 ). BM-MNCs heterogenous cell population mostly contain hematopoietic precursor cells, hemangioblasts and endothelial progenitors with no capacity to multipotent differentiation.…”