Activated SOX9+ renal epithelial cells promote kidney repair through secreting factors

Abstract

A broad spectrum of lethal kidney diseases involves the irreversible destruction of the tubular structures, leading to renal function loss. Following injury, a spectrum of tissue-resident epithelial stem/progenitor cells are known to be activated and then differentiate into mature renal cells to replace the damaged renal epithelium. Here, however, we reported an alternative way that tissue-resident cells could be activated to secrete multiple factors to promote organ repair. At single-cell resolution, we showed that the resident SOX9+ renal epithelial cells (RECs) could expand in the acutely injured kidney of both mouse and human. Compared to other cells, the SOX9+ RECs overexpressed much more secretion related genes, whose functions were linked to kidney repair pathways. We also obtained long-term, feeder-free cultured SOX9+ RECs from human urine and analysed their secretory profile at both transcriptional and proteomic levels. Engraftment of cultured human SOX9+ RECs or injection of its conditional medium facilitated the regeneration of renal tubular and glomerular epithelium, probably through stimulating endogenous REC self-activation and mediating crosstalk with other renal cells. We also identified S100A9 as one of the key factors in the SOX9+ REC secretome. Altogether, the abilities to extensively propagate SOX9+ RECs in culture whilst concomitantly maintaining their intrinsic secretory capacity suggest their future application in cell-free therapies and regeneration medicine.

Bibliometric and visualization analysis of kidney repair associated with acute kidney injury from 2002 to 2022

“…In IRI and folic acid (FA)-induced AKI models, early growth response 1 (EGR1) can increase Sox9 expression in kidney TECs by directly binding to the promoter of the Sox9 gene, consequently promoting Sox9 cell proliferation by activating the Wnt/β-catenin pathway ( Chen et al, 2022 ). A recent study found that kidney-resident Sox9+ TECs can be activated and secrete various factors to promote tissue repair, of which S100A9 may be a key factor associated with the renal repair pathway ( Nie et al, 2023 ). Although the upregulation of Sox9 was identified as an early event after AKI in these studies, the primary player in kidney repair as tubular epithelial cells or resident tubular progenitor cells remains controversial.…”

Targeted glomerular mesangium transfection by antifibrotic gene nanocarriers inhibits kidney fibrosis and promotes regeneration

“…Previous studies have implicated the activation and expansion of sex-determining region Y-box 9 (SOX9) + cells, generally termed renal progenitor cells, have been reported to play important roles in both the formation [70] and renal regeneration in adult kidney tissue. [9,[71][72][73] Furthermore, BMP7 has also been suggested to promote tubular regeneration. [28,74] Thus, we next sought to determine whether a SOX9 + cell response was responsible for the elevated cell proliferation following PCHS-NP administration to UUO kidneys.…”

Traditional Chinese Medicine and renal regeneration: experimental evidence and future perspectives

“…Recently, several studies have shown that injury-induced Sox9 activation acts as a regenerative signal. Several studies have confirmed that Sox9 + renal tubular cells have progenitor cell properties, which increase rapidly after kidney injury and then participate in the repair of kidney injury [ 19 , 21 – 23 ]. Briefly, following kidney injury, the renal tubules are initially damaged, prompting the proliferation of renal progenitor cells, which then contribute to the repair of damage.…”

“…Low Sox9 expression has been observed in adult kidneys. However, when cellular stress or injury occurs, Sox9 undergoes transcriptional activation [21][22][23]. Kumar et al discovered that in acutely injured mammalian kidneys, the activation and regulation of Sox9 are mediated by the EGFR/ERK1/2 signaling pathway and HIFA [4].…”