Vasculogenic skin reprogramming requires TET-mediated gene demethylation in fibroblasts for rescuing impaired perfusion in diabetes
Year: 2024
Type: article
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. Tissue nanotransfection (TNT) achieves non-viral vasculogenic reprogramming of the skin. Here the authors show that upregulation of TET1/2/3, limited under diabetic conditions, is effective in markedly improving TNT-induced vasculogenic outcomes thus rescuing ischemic diabetic tissue at risk.
Source: Nature Communications
Authors: 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, Chandan K. Sen
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, John Templeton Foundation, Eli Lilly and Company, Yale University, Lilly Endowment, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Congressionally Directed Medical Research Programs
Awards: Tissue reprogramming in diabetic wound healing, G1580871201, G1731027890, Vasculogenic Skin Reprogramming to Rescue Diabetic Wound Healing, G2783355966, Diabetic Foot Ulcer Biofilm Infection and Recurrence, Cell Specific Gene Editing to Close Diabetic Wounds, G3051196585, G3116351511, G3616753175, G364566446, G4119534169, G4149498297, G4229822067, G4811998624, G5631099140, G5711187628, VASCULOGENIC SKIN REPROGRAMMING TO RESCUE DIABETIC WOUND HEALING, Diabetic Foot Ulcer Clinical Research Unit, Regulatory Mechanisms Addressing Diabetic Vasculopathy, G6758582955, G720907354, G7235672785, G728465415, G7367709834, TARGETED EPIGENETIC GENE EDITING IN VIVO TO RESCUE DIABETIC ISCHEMIC WOUNDS, G7410153738, G7649923174, G777457928, G8110828221, G8196579522, ENDOTHELIAL-TARGETED METALLOTHIONEIN GENE EDITING TO ENABLE VEGF THERAPY IN RESCUING DIABETIC PRESSURE ULCER, G864424402, G8687875210, G8748435006, G8780510893, G8820008394, G8981608672
OpenAlex ID: W4404764667