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Sox9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE249781 | GEO | 2024/02/26

REPOSITORIES: GEO

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SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys.

Project description:The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), injured proximal tubular epithelial cells activate SOX9 for self-restoration. Using a multimodal approach for a head-to-head comparison of injury-induced SOX9 lineages, we identified a dynamic SOX9 switch in repairing epithelia. Lineages that regenerated epithelia silenced SOX9 and healed without fibrosis (SOX9on-off). By contrast, lineages with unrestored apicobasal polarity maintained SOX9 activity in sustained efforts to regenerate, which were identified as a SOX9on-on Cadherin6pos cell state. These reprogrammed cells generated substantial single-cell WNT activity to provoke a fibroproliferative response in adjacent fibroblasts, driving AKI to chronic kidney disease. Transplanted human kidneys displayed similar SOX9/CDH6/WNT2B responses. Thus, we have uncovered a sensor of epithelial repair status, the activity of which determines regeneration with or without fibrosis.

| S-EPMC11345873 | biostudies-literature

Sox9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys [snATAC-Seq]

Project description:The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), the injured proximal tubular epithelial cells activate Sox9 for self-restoration. Using head-to-head comparison of injury- induced Sox9-lineages via spatiotemporal mapping, single-cell sequencing, and single-nuclei chromatin accessibility profiling, we identified a dynamic SOX9 switch. Lineages that regenerated epithelia silenced SOX9 and healed without fibrosis (SOX9on-off). In contrast, lineages that maintained Sox9 activity in attempt to regenerate, demarcated by SOX9-induced Cadherin 6 (SOX9on-on CDH6pos ) cell state, generated single-cell Wnt activity to provoke a fibroproliferative response in adjacent fibroblasts, driving AKI to chronic kidney disease. Transplanted human kidneys displayed similar SOX9/CDH6/WNT2B responses post-injury. Thus, we uncovered a mechanism linking fibrosis to sustained efforts to regenerate the injured tissue.

2024-02-26 | GSE249780 | GEO

Sox9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys [CUT&Run]

2024-02-26 | GSE249776 | GEO