Mitochondria transfer from mesenchymal stem cells structurally and functionally repairs renal proximal tubular epithelial cells in diabetic nephropathy in vivo

Abstract

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.

Extracellular Vesicles, Apoptotic Bodies and Mitochondria: Stem Cell Bioproducts for Organ Regeneration

“…In the kidney, the effectiveness of AMT was demonstrated by rescue of damaged renal proximal tubular cells. In vitro, the administration of MSC-derived mitochondria reduced ROS production and increased the expression of the tubular marker megalin and mitochondrial superoxide dismutase 2, whereas in vivo, both the tubular basement membrane and brush border were protected [61]. Moreover, in normal mice, the administration of mitochondria improved endurance during forced swimming test.…”

Mesenchymal Stem/Stromal Cell-Mediated Mitochondrial Transfer and the Therapeutic Potential in Treatment of Neurological Diseases

“…The imbalance of the Bax/Bcl-2 ratio is a feature that often occurs during the process of apoptosis [29]. Mitochondrial transfer from MSCs can reduce apoptosis levels and promote cell viability in recipient cells [30] via regulating the balance of Bax/Bcl-2 and reducing the expression of caspase-3 [31]. Interestingly, transfer of dysfunctional mitochondria from damaged cells to MSCs also has an influence on MSCs.…”

Mesenchymal Stem Cells Transplantation in Diabetic Kidney Diseases: A Systematic Review and Meta-analysis

“…Experiments demonstrated that mitochondria from BM-MSCs given systematically was transferred into proximal tubular epithelial cells [42], indicating the mitochondria and its relevant functions might occupy a position in the therapeutic effect of MSCs. Mitochondria from MSCs could enhance the expression of superoxide dismutase 2 (SOD2) and Bcl-2 in vitro, inhibiting the production of reactive oxygen species (ROS) and cell apoptosis in PTECs under the condition of high glucose.…”

“…Mitochondria from MSCs could enhance the expression of superoxide dismutase 2 (SOD2) and Bcl-2 in vitro, inhibiting the production of reactive oxygen species (ROS) and cell apoptosis in PTECs under the condition of high glucose. Besides, megalin and SGLT-2 were also restored to improve blood glucose control and anti-in ammatory effect, especially the reduction of IL-16 [34,42].…”