Department of Cardiovascular-Thoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA.
J Transl Med. 2022 Jul 21;20(1):323. doi: 10.1186/s12967-022-03534-0.
Despite promising results in clinical studies, the mechanism for the beneficial effects of allogenic cell-based therapies remains unclear. Macrophages are not only critical mediators of inflammation but also critical players in cardiac remodeling. We hypothesized that transplanted allogenic rat cardiac progenitor cells (rCPCs) augment T-regulatory cells which ultimately promote proliferation of M2 like macrophages by an as-yet undefined mechanism.
To test this hypothesis, we used crossover rat strains for exploring the mechanism of myocardial repair by allogenic CPCs. Human CPCs (hCPCs) were isolated from adult patients undergoing coronary artery bypass grafting, and rat CPCs (rCPCs) were isolated from male Wistar-Kyoto (WKY) rat hearts. Allogenic rCPCs suppressed the proliferation of T-cells observed in mixed lymphocyte reactions in vitro. Transplanted syngeneic or allogeneic rCPCs significantly increased cardiac function in a rat myocardial infarct (MI) model, whereas xenogeneic CPCs did not. Allogeneic rCPCs stimulated immunomodulatory responses by specifically increasing T-regulatory cells and M2 polarization, while maintaining their cardiac recovery potential and safety profile. Mechanistically, we confirmed the inactivation of NF-kB in Treg cells and increased M2 macrophages in the myocardium after MI by transplanted CPCs derived GDF15 and it's uptake by CD48 receptor on immune cells.
Collectively, these findings strongly support the active immunomodulatory properties and robust therapeutic potential of allogenic CPCs in post-MI cardiac dysfunction.
尽管异体细胞基疗法的临床研究结果令人鼓舞，但其有益效果的机制仍不清楚。巨噬细胞不仅是炎症的关键介质，也是心脏重构的关键参与者。我们假设，移植的异体大鼠心脏祖细胞（rCPCs）可增加调节性 T 细胞，这些细胞最终通过尚未明确的机制促进 M2 样巨噬细胞的增殖。
为了验证这一假设，我们使用交叉大鼠品系来探索异体 CPC 修复心肌的机制。从接受冠状动脉旁路移植术的成年患者中分离出人 CPC（hCPCs），从雄性 Wistar-Kyoto（WKY）大鼠心脏中分离出大鼠 CPC（rCPCs）。异体 rCPC 在体外混合淋巴细胞反应中抑制 T 细胞的增殖。同种异体或异体 rCPC 显著增加了大鼠心肌梗死（MI）模型中的心脏功能，而异种 CPC 则没有。同种异体 rCPC 通过特异性增加 Treg 细胞和 M2 极化来刺激免疫调节反应，同时保持其心脏恢复潜力和安全性。从机制上讲，我们证实了移植的 CPC 衍生的 GDF15 在 Treg 细胞中 NF-kB 的失活和 MI 后心肌中 M2 巨噬细胞的增加，以及 GDF15 通过免疫细胞上的 CD48 受体的摄取。
综上所述，这些发现有力地支持了异体 CPC 在 MI 后心脏功能障碍中的主动免疫调节特性和强大的治疗潜力。
