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

Author

Listed:
  • Sujit K. Mohanty

    (University of Pittsburgh
    University of Pittsburgh
    Indiana University School of Medicine)

  • Kanhaiya Singh

    (University of Pittsburgh
    University of Pittsburgh
    Indiana University School of Medicine)

  • Manishekhar Kumar

    (University of Pittsburgh
    University of Pittsburgh
    Indiana University School of Medicine)

  • Sumit S. Verma

    (University of Pittsburgh
    University of Pittsburgh
    Indiana University School of Medicine)

  • Rajneesh Srivastava

    (University of Pittsburgh
    University of Pittsburgh
    Indiana University School of Medicine)

  • Surya C. Gnyawali

    (University of Pittsburgh
    University of Pittsburgh
    Indiana University School of Medicine)

  • Ravichand Palakurti

    (University of Pittsburgh
    University of Pittsburgh
    Indiana University School of Medicine)

  • Ajay K. Sahi

    (University of Pittsburgh
    University of Pittsburgh)

  • Mohamed S. El Masry

    (University of Pittsburgh
    University of Pittsburgh)

  • Pradipta Banerjee

    (University of Pittsburgh
    University of Pittsburgh)

  • Sedat Kacar

    (Indiana University School of Medicine)

  • Yashika Rustagi

    (Indiana University School of Medicine)

  • Priyanka Verma

    (Indiana University School of Medicine)

  • Subhadip Ghatak

    (University of Pittsburgh
    University of Pittsburgh
    Indiana University School of Medicine)

  • Edward Hernandez

    (Indiana University School of Medicine)

  • J. Peter Rubin

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Savita Khanna

    (University of Pittsburgh
    University of Pittsburgh
    Indiana University School of Medicine)

  • Sashwati Roy

    (University of Pittsburgh
    University of Pittsburgh
    Indiana University School of Medicine)

  • Mervin C. Yoder

    (University of Pittsburgh
    University of Pittsburgh
    Indiana University School of Medicine)

  • Chandan K. Sen

    (University of Pittsburgh
    University of Pittsburgh
    Indiana University School of Medicine
    University of Pittsburgh)

Abstract

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. TNTEFF 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. TNTEFF 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.

Suggested Citation

  • Sujit K. Mohanty & Kanhaiya Singh & Manishekhar Kumar & Sumit S. Verma & Rajneesh Srivastava & Surya C. Gnyawali & Ravichand Palakurti & Ajay K. Sahi & Mohamed S. El Masry & Pradipta Banerjee & Sedat , 2024. "Vasculogenic skin reprogramming requires TET-mediated gene demethylation in fibroblasts for rescuing impaired perfusion in diabetes," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54385-w
    DOI: 10.1038/s41467-024-54385-w
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    References listed on IDEAS

    as
    1. Gabriella Ficz & Miguel R. Branco & Stefanie Seisenberger & Fátima Santos & Felix Krueger & Timothy A. Hore & C. Joana Marques & Simon Andrews & Wolf Reik, 2011. "Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation," Nature, Nature, vol. 473(7347), pages 398-402, May.
    2. Thomas Graf & Tariq Enver, 2009. "Forcing cells to change lineages," Nature, Nature, vol. 462(7273), pages 587-594, December.
    Full references (including those not matched with items on IDEAS)

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