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血管生成皮肤重编程需要 TET 介导的成纤维细胞基因去甲基化，以挽救糖尿病受损的灌注。

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

机构信息

McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.

出版信息

Nat Commun. 2024 Nov 27;15(1):10277. doi: 10.1038/s41467-024-54385-w.

DOI:10.1038/s41467-024-54385-w
PMID:39604331
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11603198/
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. TNT 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 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.

摘要

组织纳米转染（TNT）局部递送 Etv2、Foxc2 和 Fli1（EFF）质粒，增加血管生成成纤维细胞（VF）并促进缺血性小鼠皮肤的血管生成。人真皮成纤维细胞对 EFF 纳米电穿孔的反应是体外内皮基因表达升高，这与十-十一转位酶 1/2/3（TET）表达增加有关。单细胞 RNA 测序依赖性验证 VF 诱导揭示了 TET 依赖性转录特征。TNT 还可在体内诱导 TET 表达，成纤维细胞特异性 EFF 过表达导致 VF 转化，TET 激活与 VF 中更高的 5-羟甲基胞嘧啶（5-hmC）水平相关。VF 的出现需要体内内皮基因的 TET 依赖性去甲基化，从而增加 VF 的丰度并恢复糖尿病性缺血肢体的灌注。TNT 可改善糖尿病小鼠的灌注和伤口闭合，并增加培养的人皮肤外植体中的 VF。在糖尿病中受到抑制，TET1/2/3 在 TNT 介导的 VF 形成中发挥关键作用，支持新血管生成以挽救糖尿病性缺血组织。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e77/11603198/775e5b24a17f/41467_2024_54385_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e77/11603198/812e2d7528e5/41467_2024_54385_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e77/11603198/4c5f303de37f/41467_2024_54385_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e77/11603198/20507effb5ff/41467_2024_54385_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e77/11603198/129413438ac9/41467_2024_54385_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e77/11603198/775e5b24a17f/41467_2024_54385_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e77/11603198/812e2d7528e5/41467_2024_54385_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e77/11603198/4c5f303de37f/41467_2024_54385_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e77/11603198/20507effb5ff/41467_2024_54385_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e77/11603198/129413438ac9/41467_2024_54385_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e77/11603198/775e5b24a17f/41467_2024_54385_Fig5_HTML.jpg

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