Piezo inhibition prevents and rescues scarring by targeting the adipocyte to fibroblast transition
Piezo inhibition prevents and rescues scarring by targeting the adipocyte to fibroblast transition
Summary While past studies have suggested that plasticity exists between dermal fibroblasts and adipocytes, it remains unknown whether fat actively contributes to fibrosis in scarring. We show that adipocytes convert to scar-forming fibroblasts in response to Piezo-mediated mechanosensing to drive wound fibrosis. We establish that mechanics alone are sufficient to drive adipocyte-to- fibroblast conversion. By leveraging clonal-lineage-tracing in combination with scRNA-seq, Visium, and CODEX, we define a “mechanically na?ve” fibroblast-subpopulation that represents a transcriptionally intermediate state between adipocytes and scar-fibroblasts. Finally, we show that Piezo1 or Piezo2-inhibition yields regenerative healing by preventing adipocytes’ activation to fibroblasts, in both mouse-wounds and a novel human-xenograft-wound model. Importantly, Piezo1-inhibition induced wound regeneration even in pre-existing established scars, a finding that suggests a role for adipocyte-to-fibroblast transition in wound remodeling, the least-understood phase of wound healing. Adipocyte-to-fibroblast transition may thus represent a therapeutic target for minimizing fibrosis via Piezo-inhibition in organs where fat contributes to fibrosis.
Griffin Michelle F.、Guardino Nicholas J.、Guo Jason L.、Chen Kellen、Mascharak Shamik、Cotterell Asha C.、Akras Deena、Berry Charlotte、Cook Jessica、Quarto Natalina、Lorenz H. Peter、Gurtner Geoffrey C.、Januszyk Michael、Parker Jennifer B.L.、Downer Mauricio、Diaz Deleon Nestor M.、Klein Ophir D.、Liang Norah、Abbas Darren B.、Talbott Heather E.、Sivaraj Dharshan、Spielman Amanda F.、King Megan、Longaker Michael T.、Wan Derrick C.、Bauer-Rowe Khristian E.、Henn Dominic、Fahy Evan J.
Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine||Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Orofacial Sciences and Program in Craniofacial Biology, University of California San FranciscoDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Orofacial Sciences and Program in Craniofacial Biology, University of California San Francisco||Department of Pediatrics, Cedars-Sinai Medical CenterDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine||Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine||Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine||Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of MedicineDepartment of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine
基础医学生物科学研究方法、生物科学研究技术生理学
adipocyteadipose tissueadipocyte plasticityfibroblastfibrosisscarringmechanotransduction
Griffin Michelle F.,Guardino Nicholas J.,Guo Jason L.,Chen Kellen,Mascharak Shamik,Cotterell Asha C.,Akras Deena,Berry Charlotte,Cook Jessica,Quarto Natalina,Lorenz H. Peter,Gurtner Geoffrey C.,Januszyk Michael,Parker Jennifer B.L.,Downer Mauricio,Diaz Deleon Nestor M.,Klein Ophir D.,Liang Norah,Abbas Darren B.,Talbott Heather E.,Sivaraj Dharshan,Spielman Amanda F.,King Megan,Longaker Michael T.,Wan Derrick C.,Bauer-Rowe Khristian E.,Henn Dominic,Fahy Evan J..Piezo inhibition prevents and rescues scarring by targeting the adipocyte to fibroblast transition[EB/OL].(2025-03-28)[2025-06-29].https://www.biorxiv.org/content/10.1101/2023.04.03.535302.点此复制
评论