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.

将骨髓来源细胞（bone marrow-derived cells, BMCs）植入心肌梗死（myocardial infarction, MI）后小鼠的心脏，可抑制心脏功能衰退。然而，针对心肌梗死后骨髓来源细胞疗法的临床试验却得到了相互矛盾的结果。尽管多数实验室实验使用健康的骨髓来源细胞供体小鼠，但临床试验则采用心肌梗死后的自体骨髓来源细胞。心肌梗死后小鼠的骨髓来源细胞治疗效能受损，这源于其细胞组成的炎性改变。因此，骨髓来源细胞的治疗效能在心肌梗死后会逐渐下降，但随着供体的炎症反应消退可得以恢复。得益于从TIME及LateTIME临床试验中获取的心肌梗死患者骨髓单个核细胞（bone marrow mononuclear cells, MNCs），我们得以验证人类心肌梗死后骨髓单个核细胞是否也会经历一段治疗效能受损的阶段。我们提出如下假说：将来自TIME临床试验患者的骨髓单个核细胞植入心肌梗死后小鼠心脏时，其治疗效果将弱于健康人类供体的骨髓单个核细胞；而来自LateTIME临床试验患者的骨髓单个核细胞则可恢复治疗特性。我们将骨髓单个核细胞分别来自健康供体、TIME临床试验患者及LateTIME临床试验患者的制剂，植入心肌梗死后的重症联合免疫缺陷（severe combined immunodeficiency, SCID）小鼠体内。健康供体组小鼠的心脏功能得到了显著改善，但TIME组与LateTIME组均未表现出治疗效果。结论：心肌梗死后人类骨髓单个核细胞缺失健康骨髓单个核细胞所具备的治疗益处，这或可部分解释为何骨髓来源细胞的临床试验结果不如动物实验成功。