Second Department of Anatomy, Sapporo Medical University, Sapporo, 060-8556, Japan.
First Department of Anatomy, Sapporo Medical University, Sapporo, 060-8556, Japan.
Sci Rep. 2019 Mar 26;9(1):5184. doi: 10.1038/s41598-019-40163-y.
The underlying therapeutic mechanism of renal tubular epithelium repair of diabetic nephropathy (DN) by bone marrow-derived mesenchymal stem cells (BM-MSCs) has not been fully elucidated. Recently, mitochondria (Mt) transfer was reported as a novel action of BM-MSCs to rescue injured cells. We investigated Mt transfer from systemically administered BM-MSCs to renal proximal tubular epithelial cells (PTECs) in streptozotocin (STZ)-induced diabetic animals. BM-MSCs also transferred their Mt to impaired PTECs when co-cultured in vitro, which suppressed apoptosis of impaired PTECs. Additionally, BM-MSC-derived isolated Mt enhanced the expression of mitochondrial superoxide dismutase 2 and Bcl-2 expression and inhibited reactive oxygen species (ROS) production in vitro. Isolated Mt also inhibited nuclear translocation of PGC-1α and restored the expression of megalin and SGLT2 under high glucose condition (HG) in PTECs. Moreover, isolated Mt directly injected under the renal capsule of STZ rats improved the cellular morphology of STZ-PTECs, and the structure of the tubular basement membrane and brush border in vivo. This study is the first to show Mt transfer from systemically administered BM-MSCs to damaged PTECs in vivo, and the first to investigate mechanisms underlying the potential therapeutic effects of Mt transfer from BM-MSCs in DN.
骨髓间充质干细胞（BM-MSCs）通过修复肾小管上皮细胞来治疗糖尿病肾病（DN）的潜在治疗机制尚未完全阐明。最近，有研究报道称线粒体（Mt）转移是 BM-MSCs 拯救受损细胞的一种新作用。我们研究了骨髓间充质干细胞在链脲佐菌素（STZ）诱导的糖尿病动物体内向肾近端小管上皮细胞（PTECs）转移 Mt 的情况。体外共培养时，BM-MSCs 也将其 Mt 转移到受损的 PTECs 中，从而抑制受损 PTECs 的凋亡。此外，BM-MSC 来源的分离 Mt 可增强线粒体超氧化物歧化酶 2 和 Bcl-2 的表达，并抑制体外活性氧（ROS）的产生。分离 Mt 还可抑制高糖条件下（HG）PGC-1α 的核转位，并恢复 PTECs 中 megalin 和 SGLT2 的表达。此外，直接将分离 Mt 注射到 STZ 大鼠的肾包膜下可改善 STZ-PTECs 的细胞形态，以及体内管状基底膜和刷状缘的结构。这项研究首次表明，骨髓间充质干细胞在体内向受损的 PTECs 转移 Mt，并且首次研究了 BM-MSCs 转移 Mt 在糖尿病肾病中的潜在治疗作用的机制。
