Sox9 and Rbpj differentially regulate endothelial to mesenchymal transition and wound scarring in murine endovascular progenitors

Jilai Zhao, Jatin Patel, Simranpreet Kaur, Seen-Ling Sim, Ho Yi Wong, Cassandra Styke, Isabella Hogan, Sam Kahler, Hamish Hamilton, Racheal Wadlow, James Dight, Ghazaleh Hashemi, Laura Sormani, Edwige Roy, Mervin C. Yoder, Mathias Francois and Kiarash Khosrotehrani ()
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Jilai Zhao: The University of Queensland Diamantina Institute, The University of Queensland
Jatin Patel: The University of Queensland Diamantina Institute, The University of Queensland
Simranpreet Kaur: The University of Queensland Diamantina Institute, The University of Queensland
Seen-Ling Sim: The University of Queensland Diamantina Institute, The University of Queensland
Ho Yi Wong: The University of Queensland Diamantina Institute, The University of Queensland
Cassandra Styke: The University of Queensland Diamantina Institute, The University of Queensland
Isabella Hogan: The University of Queensland Diamantina Institute, The University of Queensland
Sam Kahler: The University of Queensland Diamantina Institute, The University of Queensland
Hamish Hamilton: The University of Queensland Diamantina Institute, The University of Queensland
Racheal Wadlow: The University of Queensland Diamantina Institute, The University of Queensland
James Dight: The University of Queensland Diamantina Institute, The University of Queensland
Ghazaleh Hashemi: The University of Queensland Diamantina Institute, The University of Queensland
Laura Sormani: The University of Queensland Diamantina Institute, The University of Queensland
Edwige Roy: The University of Queensland Diamantina Institute, The University of Queensland
Mervin C. Yoder: Indiana Center for Regenerative Medicine and Engineering
Mathias Francois: The David Richmond Laboratory for Cardiovascular Development: Gene Regulation and Editing Program, The Centenary Institute
Kiarash Khosrotehrani: The University of Queensland Diamantina Institute, The University of Queensland

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Endothelial to mesenchymal transition (EndMT) is a leading cause of fibrosis and disease, however its mechanism has yet to be elucidated. The endothelium possesses a profound regenerative capacity to adapt and reorganize that is attributed to a population of vessel-resident endovascular progenitors (EVP) governing an endothelial hierarchy. Here, using fate analysis, we show that two transcription factors SOX9 and RBPJ specifically affect the murine EVP numbers and regulate lineage specification. Conditional knock-out of Sox9 from the vasculature (Sox9fl/fl/Cdh5-CreER RosaYFP) depletes EVP while enhancing Rbpj expression and canonical Notch signalling. Additionally, skin wound analysis from Sox9 conditional knock-out mice demonstrates a significant reduction in pathological EndMT resulting in reduced scar area. The converse is observed with Rbpj conditionally knocked-out from the murine vasculature (Rbpjfl/fl/Cdh5-CreER RosaYFP) or inhibition of Notch signaling in human endothelial colony forming cells, resulting in enhanced Sox9 and EndMT related gene (Snail, Slug, Twist1, Twist2, TGF-β) expression. Similarly, increased endothelial hedgehog signaling (Ptch1fl/fl/Cdh5-CreER RosaYFP), that upregulates the expression of Sox9 in cells undergoing pathological EndMT, also results in excess fibrosis. Endothelial cells transitioning to a mesenchymal fate express increased Sox9, reduced Rbpj and enhanced EndMT. Importantly, using topical administration of siRNA against Sox9 on skin wounds can substantially reduce scar area by blocking pathological EndMT. Overall, here we report distinct fates of EVPs according to the relative expression of Rbpj or Notch signalling and Sox9, highlighting their potential plasticity and opening exciting avenues for more effective therapies in fibrotic diseases.

Date: 2021
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DOI: 10.1038/s41467-021-22717-9

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