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

Shikhar Aggarwal; Zhanxiang Wang; David Rincon Fernandez Pacheco; Anna Rinaldi; Alex Rajewski; Jasper Callemeyn; Elisabet Van Loon; Baptiste Lamarthée; Ambart Ester Covarrubias; Jean Hou; Michifumi Yamashita; Haruhiko Akiyama; S Ananth Karumanchi; Clive N Svendsen; Paul W Noble; Stanley C Jordan; Joshua J Breunig; Maarten Naesens; Pietro E Cippà; Sanjeev Kumar

doi:10.1126/science.add6371

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

Science. 2024 Feb 23;383(6685):eadd6371. doi: 10.1126/science.add6371. Epub 2024 Feb 23.

Authors

Shikhar Aggarwal^#^{1

2}, Zhanxiang Wang^#^{1

2}, David Rincon Fernandez Pacheco^#^{1

2}, Anna Rinaldi³, Alex Rajewski⁴, Jasper Callemeyn⁵, Elisabet Van Loon⁵, Baptiste Lamarthée⁵, Ambart Ester Covarrubias⁶, Jean Hou⁷, Michifumi Yamashita⁷, Haruhiko Akiyama⁸, S Ananth Karumanchi^{2

6}, Clive N Svendsen^{1

2}, Paul W Noble⁹, Stanley C Jordan⁶, Joshua J Breunig^{1

2}, Maarten Naesens⁵, Pietro E Cippà^{3

10}, Sanjeev Kumar^{1

2

6}

Affiliations

¹ Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
² Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
³ Division of Nephrology, Ente Ospedaliero Cantonale, CH-6900 Lugano, Switzerland.
⁴ Applied Genomics, Computation, and Translational Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁵ Department of Microbiology, Immunology and Transplantation, KU Leuven, BE-3000 Leuven, Belgium.
⁶ Division of Nephrology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁷ Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁸ Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
⁹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁰ Faculty of Biomedical Sciences, Università della Svizzera Italiana, CH-6900 Lugano, Switzerland.

^# Contributed equally.

PMID: 38386758
DOI: 10.1126/science.add6371

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^on-off). By contrast, lineages with unrestored apicobasal polarity maintained SOX9 activity in sustained efforts to regenerate, which were identified as a SOX9^on-on Cadherin6^pos 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.

MeSH terms

Acute Kidney Injury* / genetics
Acute Kidney Injury* / pathology
Animals
Epithelial Cells
Fibrosis
Humans
Kidney* / pathology
Mice
Regeneration
Renal Insufficiency, Chronic* / genetics
Renal Insufficiency, Chronic* / pathology
SOX9 Transcription Factor* / genetics

Substances

SOX9 protein, human
SOX9 Transcription Factor