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Isolation and Culture of Cells from the Nephrogenic Zone of the Embryonic Mouse Kidney
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SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys

Shikhar Aggarwal1,2, Zhanxiang Wang1,2, David Rincon Fernandez Pacheco1,2

  • 1Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Science (New York, N.Y.)
|February 22, 2024
PubMed

Insights

Scientists discovered a SOX9 switch in kidney cells that determines healing after injury. SOX9 silencing leads to fibrosis-free repair, while sustained SOX9 activity drives chronic kidney disease progression.

Area of Science:

  • Nephrology
  • Cell Biology
  • Regenerative Medicine

Background:

  • The mechanisms of kidney healing versus fibrosis after acute kidney injury (AKI) remain incompletely understood.
  • Injured proximal tubular epithelial cells initiate self-repair by activating SOX9.

Purpose of the Study:

  • To compare injury-induced SOX9 cell lineages and elucidate their roles in kidney repair and fibrosis.
  • To identify the molecular determinants of fibrosis-free regeneration versus fibrotic scarring in AKI.

Main Methods:

  • Multimodal analysis of SOX9 cell lineages following kidney injury.
  • Single-cell analysis of epithelial repair states and associated signaling pathways.
  • Investigation of SOX9, Cadherin 6 (CDH6), and WNT pathway interactions.
  • Validation in human kidney transplant samples.

Main Results:

  • Two distinct SOX9 epithelial repair lineages were identified: SOX9-off (fibrosis-free healing) and SOX9-on (fibrotic response).
  • Sustained SOX9 activity, termed SOX9-on Cadherin6-positive (CDH6pos) state, promotes aberrant regeneration.
  • This CDH6pos state drives WNT signaling, inducing fibroblast activation and fibrosis, progressing AKI to chronic kidney disease.
  • Similar SOX9/CDH6/WNT2B responses were observed in human transplanted kidneys.

Conclusions:

  • SOX9 acts as a critical sensor of epithelial repair status, dictating kidney healing outcomes.
  • Silencing SOX9 promotes successful regeneration without fibrosis.
  • Persistent SOX9 activation drives fibrotic responses and chronic kidney disease development.
  • Targeting the SOX9 pathway may offer therapeutic strategies for preventing kidney fibrosis.

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