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.
Highlights
Autologous cell therapy after myocardial infarction (MI), for the purpose of repairing damaged regions or preserving tissue at risk, is the focus of intense research and debate
We hypothesized that human BM mononuclear cells (MNCs) harvested at 3 or 7 days post-MI are therapeutically impaired and that human bone marrow mononuclear cells (BM MNCs) harvested 3 weeks post-MI are less impaired, based on results from our mouse-to-mouse experiments in which a progressive impairment of bone marrow-derived cells (BMCs) occurred over the first week post-MI, followed by a partial return to normalcy at 21 days postMI [12]
Recipient mouse cardiac function represented by left ventricular ejection fraction (LVEF), End-systolic volume (ESV) and end-diastolic volume (EDV) was assessed by echocardiography
Summary
Autologous cell therapy after myocardial infarction (MI), for the purpose of repairing damaged regions or preserving tissue at risk, is the focus of intense research and debate. Delivery of various populations of bone marrow-derived cells (BMCs) to the infarcted myocardium has been reported to improve post-MI cardiac function in most preclinical experiments, despite debate about the underlying mechanisms [1]. We further showed that the timing of the appearance and resolution of the postMI acute inflammatory response correlated with a decline and recovery in BMC therapeutic efficacy, with a progressive impairment of BMCs observed over the first week post-MI, followed by a partial return to normalcy by 21 days post-MI. In humans, this has not been evaluated
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