Adipose-derived mesenchymal stem cells employed exosomes to attenuate AKI-CKD transition through tubular epithelial cell dependent Sox9 activation

Abstract

Acute kidney injury (AKI) predisposes patients to an increased risk into progressive chronic kidney disease (CKD), however effective treatments are still elusive. This study aimed to investigate the therapeutic efficacy of human adipose-derived MSCs (hAD-MSCs) in the prevention of AKI-CKD transition, and illuminate the role of Sox9, a vital transcription factor in the development of kidney, in this process. C57BL/6 mice were subjected to unilateral renal ischemia/reperfusion (I/R) with or without hAD-MSC treatment. We found that hAD-MSC treatment upregulated the expression of tubular Sox9, promoted tubular regeneration, attenuated AKI, and mitigated subsequent renal fibrosis. However, these beneficial effects were abolished by a drug inhibiting the release of exosomes from hAD-MSCs. Similarly, Sox9 inhibitors reversed these protective effects. Further, we verified that hAD-MSCs activated tubular Sox9 and prevented TGF-β1-induced transformation of TECs into pro-fibrotic phenotype through exosome shuttling in vitro, but the cells did not inhibit TGF-β1-induced transition of fibroblasts into myofibroblasts. Inhibiting the release of exosomes from hAD-MSCs or the expression of Sox9 in TECs reversed these antifibrotic effects. In conclusion, hAD-MSCs employed exosomes to mitigate AKI-CKD transition through tubular epithelial cell dependent activation of Sox9.

Exosomal miRNA-215-5p Derived from Adipose-Derived Stem Cells Attenuates Epithelial–Mesenchymal Transition of Podocytes by Inhibiting ZEB2

“…Human urine stem cell-derived exosomes (USCs-Exo) reduce the apoptosis of podocytes and renal tubular epithelial cells and increase the proliferation of glomerular endothelial cells, leading to the decline of proteinuria excretion in DN rats [11]. Adipose-derived stem cell exosomes (ADSCs-Exos) effectively counter renal injury caused by acute ischemia injury [12] and attenuate chronic kidney disease (CKD) transition from acute kidney injury (AKI) by promoting tubular regeneration through activating Sox9 in renal tubular epithelial cells [13]. It has been identified that certain miRNA of stem cells is the main content which contributes to stem cell reprogramming and differentiation [14,15].…”

Extracellular Vesicles as Mediators of Cellular Crosstalk Between Immune System and Kidney Graft

“…Trophic factors carried in MSC-EVs depend on the parental cell and the surrounding milieu, such as inflammation and hypoxia (136,164,195).…”

“…Hypoxia has a profound impact on EV properties. In general, ischemic conditioning (preconditioning, postconditioning, and remote conditioning) provides positive results in the setting of myocardial infarction, and hypoxic EVs appear to mediate these effects (124,125,195).…”

Exosomes: The New Mediator of Peritoneal Membrane Function

“…Accumulating evidences showed that epithelial cells, mast cells, fibroblasts and adipocytes can produce increased numbers of exosomes [12,15,17,51,52]. In fact, the PM consists of three layers, including the mesothelial monolayer and loose adipose tissue.…”