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.

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 Tubules, Proximal* / cytology
Kidney Tubules, Proximal* / metabolism
Kidney* / pathology
Mice
Regeneration
Renal Insufficiency, Chronic* / genetics
Renal Insufficiency, Chronic* / pathology
SOX9 Transcription Factor* / genetics

Substances

SOX9 protein, human
SOX9 Transcription Factor

Grants and funding

R01 DK118265/DK/NIDDK NIH HHS/United States