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

• Published in: PloS one Vol. 15; no. 8; p. e0237401
• Main Authors: Wang, Xiaoyin, Chacon, Lourdes I., Derakhshandeh, Ronak, Rodriguez, Hilda J., Han, Daniel D., Kostyushev, Dmitry S., Henry, Timothy D., Traverse, Jay H., Moyé, Lem, Simari, Robert D., Taylor, Doris A., Springer, Matthew L.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.08.2020; Public Library of Science (PLoS)
• Subjects: Animals; Autografts; Biology and Life Sciences; Bone marrow; Bone marrow cells; Bone Marrow Transplantation; Cardiac function; Cardiology; Care and treatment; Chemical compounds; Clinical trials; Clinical Trials as Topic; Complications and side effects; Coronary vessels; Engineering and Technology; Experiments; Health aspects; Health care; Heart; Heart attack; Heart attacks; Hospitals; Human subjects; Implantation; Inflammation; Inflammatory response; Laboratory animals; Laboratory experiments; Leukocytes (mononuclear); Male; Medical research; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; MicroRNAs; MicroRNAs - genetics; Mortality; Myocardial infarction; Myocardial Infarction - genetics; Myocardial Infarction - therapy; Patient outcomes; Patients; Pharmaceuticals; Research and Analysis Methods; Stem cell transplantation; Stem cells; Surgery; Treatment Outcome; Ultrasonic imaging; United States; San Francisco California; California; United States > US; Texas
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0237401

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.