Vasculogenic skin reprogramming requires TET-mediated gene demethylation in fibroblasts for rescuing impaired perfusion in diabetes.

Autor: Mohanty SK; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Singh K; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Kumar M; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Verma SS; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Srivastava R; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Gnyawali SC; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Palakurti R; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Sahi AK; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA., El Masry MS; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA., Banerjee P; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA., Kacar S; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Rustagi Y; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Verma P; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Ghatak S; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Hernandez E; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Rubin JP; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA., Khanna S; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Roy S; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Yoder MC; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA., Sen CK; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA. c.k.sen@pitt.edu.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. c.k.sen@pitt.edu.; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA. c.k.sen@pitt.edu.; Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA. c.k.sen@pitt.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Nov 27; Vol. 15 (1), pp. 10277. Date of Electronic Publication: 2024 Nov 27.
DOI: 10.1038/s41467-024-54385-w
Abstrakt: Tissue nanotransfection (TNT) topically delivers Etv2, Foxc2, and Fli1 (EFF) plasmids increasing vasculogenic fibroblasts (VF) and promoting vascularization in ischemic murine skin. Human dermal fibroblasts respond to EFF nanoelectroporation with elevated expression of endothelial genes in vitro, which is linked to increased ten-eleven translocase 1/2/3 (TET) expression. Single cell RNA sequencing dependent validation of VF induction reveals a TET-dependent transcript signature. TNT EFF also induces TET expression in vivo, and fibroblast-specific EFF overexpression leads to VF-transition, with TET-activation correlating with higher 5-hydroxymethylcytosine (5-hmC) levels in VF. VF emergence requires TET-dependent demethylation of endothelial genes in vivo, enhancing VF abundance and restoring perfusion in diabetic ischemic limbs. TNT EFF improves perfusion and wound closure in diabetic mice, while increasing VF in cultured human skin explants. Suppressed in diabetes, TET1/2/3 play a critical role in TNT-mediated VF formation which supports de novo blood vessel development to rescue diabetic ischemic tissue.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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