HucMSC-Derived Exosomes Preserve Mafb-Dependent Tubular Epithelial Identity and Suppress Dedifferentiation in Obstructive Nephropathy.

Abstract

Tubular epithelial dedifferentiation and loss of polarity are early pathological events in obstructive nephropathy and critically contribute to progressive renal fibrosis. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSC-Exos) have shown therapeutic potential for kidney injury, yet the mechanisms by which they preserve epithelial identity remain unclear. Mafb, a transcription factor essential for renal epithelial differentiation, has been implicated in epithelial homeostasis, but its role in adult obstructive injury and its regulation by exosomes are unknown. Here, a unilateral ureteral obstruction (UUO) mouse model was used to evaluate early tubular injury and the effects of HucMSC-Exos. UUO induced marked epithelial damage characterized by decreased E-cadherin, increased vimentin and α-smooth muscle actin (α-SMA) expression, and disruption of epithelial polarity, whereas HucMSC-Exo administration significantly ameliorated these alterations. Mafb expression was profoundly downregulated in UUO kidneys but was effectively restored following exosome treatment. In vitro, Mafb knockdown in Human renal proximal tubular epithelial (HK-2) cells markedly aggravated TGF-β1-induced dedifferentiation, confirming its protective role in epithelial integrity. Analysis of Mafb ^-/- embryonic kidneys demonstrated severe developmental defects and loss of polarity markers, highlighting the essential function of Mafb in renal epithelium. Importantly, HucMSC-Exos rescued epithelial marker expression even in Mafb-silenced cells, suggesting both Mafb-dependent and independent mechanisms. These findings identify Mafb as a key regulator of tubular epithelial homeostasis and reveal that HucMSC-Exos attenuate early renal injury partly through Mafb restoration.