Key Laboratory of Transplant Engineering and Immunology, NHFPC, Department of Nephrology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
Stem Cells. 2021 Jul;39(7):913-928. doi: 10.1002/stem.3375. Epub 2021 Apr 16.
Mesenchymal stem cells (MSCs) have fueled ample translation for treatment of immune-mediated diseases. Our previous study had demonstrated that MSCs could elicit macrophages (Mφ) into anti-inflammatory phenotypes, and alleviate kidney injury in diabetic nephropathy (DN) mice via improving mitochondrial function of Mφ, yet the specific mechanism was unclear. Recent evidence indicated that MSCs communicated with their microenvironment through exchanges of mitochondria. By a coculture system consisting of MSCs and Mφ, we showed that MSCs-derived mitochondria (MSCs-Mito) were transferred into Mφ, and the mitochondrial functions were improved, which contributed to M2 polarization. Furthermore, we found that MSCs-Mito transfer activated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis. In addition, PGC-1α interacted with TFEB in high glucose-induced Mφ, leading to the elevated lysosome-autophagy, which was essential to removal of damaged mitochondria. As a result, in Mφ, the mitochondrial bioenergy and capacity to combat inflammatory response were enhanced. Whereas, the immune-regulatory activity of MSCs-Mito was significantly blocked in PGC-1α knockdown Mφ. More importantly, MSCs-Mito transfer could be observed in DN mice, and the adoptive transfer of MSCs-Mito educated Mφ (Mφ ) inhibited the inflammatory response and alleviated kidney injury. However, the kidney-protective effects of Mφ were abolished when the MSCs-Mito was impaired with rotenone, and the similar results were also observed when Mφ were transfected with sipgc-1α before administration. Collectively, these findings suggested that MSCs elicited Mφ into anti-inflammatory phenotype and ameliorated kidney injury through mitochondrial transfer in DN mice, and the effects were relied on PGC-1α-mediated mitochondrial biogenesis and PGC-1α/TFEB-mediated lysosome-autophagy.
间充质干细胞 (MSCs) 在治疗免疫介导性疾病方面取得了丰硕的转化成果。我们之前的研究表明，MSCs 可以通过改善 Mφ 的线粒体功能将巨噬细胞 (Mφ) 诱导为抗炎表型，从而减轻糖尿病肾病 (DN) 小鼠的肾损伤，但具体机制尚不清楚。最近的证据表明，MSCs 通过线粒体交换与微环境进行通讯。通过 MSCs 和 Mφ 的共培养系统，我们表明 MSCs 衍生的线粒体 (MSCs-Mito) 被转移到 Mφ 中，并改善了线粒体功能，促进了 M2 极化。此外，我们发现 MSCs-Mito 转移激活了过氧化物酶体增殖物激活受体γ共激活因子 1α (PGC-1α) 介导的线粒体生物发生。此外，PGC-1α 在高糖诱导的 Mφ 中与 TFEB 相互作用，导致溶酶体自噬增加，这对于清除受损线粒体至关重要。因此，在 Mφ 中，线粒体生物能量和对抗炎症反应的能力得到增强。然而，PGC-1α 敲低的 Mφ 中 MSCs-Mito 的免疫调节活性显著受阻。更重要的是，在 DN 小鼠中可以观察到 MSCs-Mito 的转移，而 MSCs-Mito 转导的 Mφ 的适应性转移（Mφ）抑制了炎症反应并减轻了肾损伤。然而，当用鱼藤酮损伤 MSCs-Mito 时，Mφ 的肾脏保护作用被消除，并且在给予 Mφ 之前用 sipgc-1α 转染 Mφ 时也观察到类似的结果。总之，这些发现表明，MSCs 通过线粒体转移在 DN 小鼠中诱导 Mφ 向抗炎表型，并改善肾损伤，其作用依赖于 PGC-1α 介导的线粒体生物发生和 PGC-1α/TFEB 介导的溶酶体自噬。
