SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38386758.
- Also identified by DOI 10.1126/science.add6371 and PMC identifier 11345873.
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Abstract
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 (SOX9<sup>on-off</sup>). By contrast, lineages with unrestored apicobasal polarity maintained SOX9 activity in sustained efforts to regenerate, which were identified as a SOX9<sup>on-on</sup> Cadherin6<sup>pos</sup> 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.
Medical subject headings
- Acute Kidney Injury
- Kidney
- Renal Insufficiency, Chronic
- SOX9 Transcription Factor
- Kidney Tubules, Proximal