William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
Basic Res Cardiol. 2019 Aug 1;114(5):34. doi: 10.1007/s00395-019-0742-1.
Reparative macrophages play an important role in cardiac repair post-myocardial infarction (MI). Bone marrow mononuclear cells (BM-MNCs) have been investigated as a donor for cell therapy but with limited clinical success. These cells, however, may be utilized as a source for reparative macrophages. This translational study aimed to establish a robust in vitro protocol to produce functional reparative macrophages from BM-MNCs and to establish pre-clinical evidence of the efficacy of reparative macrophage transplantation for the treatment of MI. Mouse BM-MNCs were treated with M-CSF plus IL-4, IL-10, TGF-β1 or combinations of these in vitro. The concomitant administration of M-CSF and IL-4 produced the highest rate and largest number of CD11bF4/80CD206 reparative macrophages. Expression and secretion of tissue repair-related factors including IGF-1, TGF-β1, VEGF and IL1-ra were remarkably enhanced in reparative macrophages compared to BM-MNCs. These cells were transplanted in a mouse MI model, resulting in evident improvement in cardiac function recovery, compared to BM-MNC transplantation. Histological studies showed that reparative macrophage transplantation enhanced myocardial tissue repair including augmented microvascular formation, reduced cardiomyocyte hypertrophy and attenuated interstitial fibrosis. Moreover, survival of reparative macrophages in the heart post-transplantation was increased compared to BM-MNCs. Reparative macrophage transplantation also increased host-derived reparative macrophages in part through TGF-β secretion. In conclusion, concomitant M-CSF + IL-4 treatment effectively produced reparative macrophages from BM-MNCs in vitro. Transplantation of produced reparative macrophage achieved a superior therapeutic efficacy, compared to BM-MNC transplantation, through the enhanced quantity and quality of donor cell engraftment. Further development of this advanced cell-based therapy is warranted.
修复性巨噬细胞在心肌梗死后的心脏修复中发挥重要作用。骨髓单核细胞（BM-MNCs）已被研究作为细胞治疗的供体，但临床效果有限。然而，这些细胞可以作为修复性巨噬细胞的来源。这项转化研究旨在建立一种从 BM-MNCs 产生功能性修复性巨噬细胞的稳健体外方案，并为修复性巨噬细胞移植治疗心肌梗死的临床前疗效提供证据。将小鼠 BM-MNCs 用 M-CSF 加 IL-4、IL-10、TGF-β1 或这些因子的组合进行体外处理。同时给予 M-CSF 和 IL-4 可产生最高比率和最大数量的 CD11bF4/80CD206 修复性巨噬细胞。与 BM-MNC 相比，修复性巨噬细胞中组织修复相关因子（包括 IGF-1、TGF-β1、VEGF 和 IL1-ra）的表达和分泌显著增强。将这些细胞移植到小鼠心肌梗死模型中，与 BM-MNC 移植相比，明显改善了心脏功能的恢复。组织学研究表明，修复性巨噬细胞移植通过增强微血管形成、减少心肌细胞肥大和减轻间质纤维化来增强心肌组织修复。此外，与 BM-MNC 相比，移植后修复性巨噬细胞在心脏中的存活率增加。修复性巨噬细胞移植还通过 TGF-β 分泌增加了宿主来源的修复性巨噬细胞。总之，同时用 M-CSF+IL-4 处理可有效从 BM-MNCs 体外产生修复性巨噬细胞。与 BM-MNC 移植相比，移植产生的修复性巨噬细胞通过增强供体细胞植入的数量和质量，实现了更好的治疗效果。进一步开发这种先进的细胞治疗方法是必要的。
