A Large-Scale Investigation of Hypoxia-Preconditioned Allogeneic Mesenchymal Stem Cells for Myocardial Repair in Non-Human Primates: Paracrine Activity Without Remuscularization
Rationale: The effectiveness of transplanted bone marrow mesenchymal stem cells (MSCs) for cardiac repair has been limited; thus, strategies for optimizing stem-cell based myocardial therapy are needed.
Objective: The present study was designed to test our central hypothesis that hypoxia preconditioned MSCs (HP-MSCs) are more effective than MSCs cultured under ambient oxygen levels (N-MSCs) for the treatment of myocardial injury in a large-scale (N=49), long-term (9 months), non-human primate (Cynomolgous monkeys) investigation.
Methods and Results: MSCs were engineered to express green fluorescent protein, cultured under ambient oxygen (N-MSCs) or 0.5% oxygen (HP-MSCs) for 24 hours, and then tested in the infarcted hearts of Cynomolgus monkeys(1×107 cells per heart). HP increased the expression of several pro-survival/pro-angiogenic factors in cultured MSCs, and measurements of infarct size and left-ventricular function at Day 90 after myocardial infarction (MI) were significantly more improved in monkeys treated with HP-MSCs than in monkeys treated with the control vehicle; functional improvements in N-MSCs-treated monkeys were not significant. HP-MSCs transplantation was also associated with increases in cardiomyocyte proliferation, vascular density, myocardial glucose uptake, and engraftment of the transplanted cells, and with declines in endogenous cell apoptosis, but did not increase the occurrence of arrhythmogenic complications.
Conclusions: HP improved the effectiveness of MSCs transplantation for the treatment of MI in nonhuman primates without increasing the occurrence of arrhythmogenic complications, which suggests that future clinical trials of HP-MSCs transplantation are warranted.
- Received August 30, 2015.
- Revision received December 30, 2015.
- Accepted January 19, 2016.
Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.