Sox9-Positive Progenitor Cells Play a Key Role in Renal Tubule Epithelial Regeneration in Mice

Abstract

The kidney has a tremendous capacity to regenerate following injury, but factors that govern this response are still largely unknown. We isolated cells from mouse kidneys with high proliferative and multi-lineage differentiation capacity. These cells expressed high level of Sox9. In regenerating kidneys, Sox9 expression was induced early and 89% of proliferating cells were Sox9 positive. In vitro, Sox9 positive cells showed unlimited proliferation and multi-lineage differentiation capacity. Using an inducible Sox9 cre line and lineage tagging methods, we show that Sox9 positive cells can supply new daughter cells, contributing to the regeneration of proximal tubule, loop of Henle and distal tubule segments, but not to collecting duct and glomerular cells. Furthermore, inducible deletion of Sox9 resulted in reduced epithelial proliferation, more severe injury and fibrosis development. In summary, we demonstrate that in the kidney, Sox9 positive cells show progenitor-like properties in vitro, and contribute to epithelial regeneration following injury in vivo.

Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog

“…Cells expressing high levels of Sox9 show progenitor cell-like characteristics including proliferation and differentiation capacity 62–64 . Renin-positive, CD133 + or slowly cycling medullary cells have also been shown to have progenitor properties 65,66 .…”

“…Renin-positive, CD133 + or slowly cycling medullary cells have also been shown to have progenitor properties 65,66 . Although the relationship between Sox9 and renin expressing progenitor cells is unclear, they both have higher Notch expression compared to differentiated tubule epithelial cells 60,64 .…”

“…For example, in response to tubule epithelial cell injury, Sox9 + cells proliferate and differentiate into different tubule segments 64 . Increasing Notch expression in Sox9 + cells accelerated epithelial repair in a mouse model of folic acid-induced kidney injury 64 .…”

Progression of chronic kidney disease: too much cellular talk causes damage

“…The Wnt/β-catenin pathway is implicated in epithelial repair, but studies also show that Wnt signaling mediates tubulointerstitial communication that promotes fibrosis(45, 46). The Wnt pathway consists of 19 Wnt ligands which bind to Frizzled and LRP5/6 receptors leading to canonical signaling through β-catenin nuclear localization and stimulation of Wnt target genes.…”

Fibrotic Changes Mediating Acute Kidney Injury to Chronic Kidney Disease Transition

“…These Sox9+ injured PT cells are actively proliferating, with half of Sox9+ cells co-expressing Kim-1 [7]. Indeed, Kang et al showed that Sox9+ cells contributed to repair of proximal, distal and loop of Henle segments after folic acid injury and IRI [8]. Using the Sox9 driven Cre-ER 2 model crossed with R26R-tdTomato, Kumar et al showed that PT cells that initiated de novo expression of Sox9 after injury, contributed the most to repair, further implicating dedifferentiation as the predominant mechanism of epithelial repair [7].…”