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

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.