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Histone deacetylase 6 promotes skin wound healing by regulating fibroblast migration and differentiation in aged mice

QIN Yu-Mei¹, LI Ping¹, MU Xue-Pan¹, LI Zhi-Min¹, SUN Chen¹, XUE Wen-Long¹, SUN Jiao², BAI Jiao-Jiao², ZHU Yi-Chun¹, WANG Ming-Jie^1,*

¹Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, the Innovative Research Team of High-level Local Universities in Shanghai, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China；²Department of Endocrinology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China

Abstract

Skin wound healing tends to slow down with aging, which is detrimental to both minor wound recovery in daily life and the recovery after surgery. The aim of current study was to explore the effect of histone deacetylase 6 (HDAC6) on wound healing during aging. Cultured human dermal fibroblasts (HDFs) and mouse full-thickness skin wound model were used to explore the functional changes of replicative senescent dermal fibroblasts and the effect of aging on skin wound healing. Scratch wound healing assay revealed significantly decreased migration speed of senescent HDFs, and BrdU incorporation assay indicated their considerably retardant proliferation. The protein expression levels of collagen and HDAC6 were significantly decreased in both senescent HDFs and skin tissues from aged mice. HDAC6 activity inhibition with highly selective inhibitor tubastatin A (TsA) or HDAC6 knockdown with siRNA decreased the migration speed of HDFs and considerably suppressed fibroblast differentiation induced by transforming growth factor-β1 (TGF-β1), which suggests the involvement of HDAC6 in regulating fundamental physiological activities of dermal fibroblasts. In vivo full-thickness skin wound healing was significantly delayed in young HDAC6 knockout mice when compared with young wild type mice. In addition, the wound healing was significantly slower in aged wild type mice than that in young wild type mice, and became even worse in aged HDAC6 knockout aged mice. Compared to the aged wild type mice, aged HDAC6 knockout mice exhibited delayed angiogenesis, reduced collagen synthesis, and decreased collagen deposition in skin wounds. Together, these results suggest that delayed skin wound healing in aged mice is associated with impaired fibroblast function. Adequate expression and activity of HDAC6 are required for fibroblasts migration and differentiation.

Key words: skin wound healing; fibroblast migration; fibroblast differentiation; aging; histone deacetylase 6

Received: 　　Accepted:

Corresponding author: 王铭洁　　E-mail: mjwang@shmu.edu.cn

Citing This Article：

QIN Yu-Mei, LI Ping, MU Xue-Pan, LI Zhi-Min, SUN Chen, XUE Wen-Long, SUN Jiao, BAI Jiao-Jiao, ZHU Yi-Chun, WANG Ming-Jie. Histone deacetylase 6 promotes skin wound healing by regulating fibroblast migration and differentiation in aged mice. Acta Physiol Sin 2022; 74 (6): 979-992