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Science ; 383(6685): eadd6371, 2024 Feb 23.
Article in English | MEDLINE | ID: mdl-38386758

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 (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.


Subject(s)
Acute Kidney Injury , Kidney Tubules, Proximal , Kidney , Renal Insufficiency, Chronic , SOX9 Transcription Factor , Animals , Humans , Mice , Acute Kidney Injury/genetics , Acute Kidney Injury/pathology , Epithelial Cells , Fibrosis , Kidney/pathology , Regeneration , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/pathology , SOX9 Transcription Factor/genetics , Kidney Tubules, Proximal/cytology , Kidney Tubules, Proximal/metabolism
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