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

  • Aggarwal, Shikhar;
  • Wang, Zhanxiang;
  • Rincon Fernandez Pacheco, David;
  • Rinaldi, Anna;
  • Rajewski, Alex;
  • Callemeyn, Jasper;
  • Van Loon, Elisabet;
  • Lamarthee, Baptiste;
  • Covarrubias, Ambart Ester;
  • Hou, Jean;
  • Yamashita, Michifumi;
  • Akiyama, Haruhiko;
  • Karumanchi, S. Ananth;
  • Svendsen, Clive N.;
  • Noble, Paul W.;
  • Jordan, Stanley C.;
  • Breunig, Joshua J.;
  • Naesens, Maarten; 50272;
  • Cippa, Pietro E.;
  • Kumar, Sanjeev;
Publication Date
Feb 23, 2024
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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. / status: published

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