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

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 Kacar, Yashika Rustagi, Priyanka Verma, Subhadip Ghatak, Edward Hernandez, J. Peter Rubin, Savita Khanna, Sashwati Roy, Mervin C. Yoder and Chandan K. Sen ()
Additional contact information
Sujit K. Mohanty: University of Pittsburgh
Kanhaiya Singh: University of Pittsburgh
Manishekhar Kumar: University of Pittsburgh
Sumit S. Verma: University of Pittsburgh
Rajneesh Srivastava: University of Pittsburgh
Surya C. Gnyawali: University of Pittsburgh
Ravichand Palakurti: University of Pittsburgh
Ajay K. Sahi: University of Pittsburgh
Mohamed S. El Masry: University of Pittsburgh
Pradipta Banerjee: 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
Edward Hernandez: Indiana University School of Medicine
J. Peter Rubin: University of Pittsburgh
Savita Khanna: University of Pittsburgh
Sashwati Roy: University of Pittsburgh
Mervin C. Yoder: University of Pittsburgh
Chandan K. Sen: University of Pittsburgh

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54385-w

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