SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys.
Science
; 383(6685): eadd6371, 2024 Feb 23.
Article
in En
| 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Renal Insufficiency, Chronic
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SOX9 Transcription Factor
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Acute Kidney Injury
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Kidney
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Kidney Tubules, Proximal
Limits:
Animals
/
Humans
Language:
En
Journal:
Sci. (N.Y., N.Y.)
/
Science
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: