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

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.

Study on synergistic inhibitory effect of ruxolitinib and decitabine on growth of HEL cells with TET2 knockdown / 中国药理学通报

Aim To explore the cytotoxic and synergistic effects of decitabine and ruxolitinib on HEL cells with TET2 knockdown. Methods Stable TET2 knockdown by shRNA was established in HEL cell line. The change of cell proliferation was measured by CCK-8 assay. The median lethal dose (IC50) and colony formation assay were used to evaluate the cytotoxic effects of decitabine and ruxolitinib, the synergistic effects of which was further analyzed by Chou-Talalay method. Results The inhibition of TET2 increased the proliferative capacity of HEL cells. HEL cell lines became resistant to decitabine following shRNA-media- ted TET2 inactivation. Colony formation assay showed that the drug sensitivity of decitabine and ruxolitinib both decreased in TET2 knockdown HEL cells. The synergistic inhibitory effects of ruxolitinib and decitabine on TET2 knockdown HEL cells were observed. Conclusion The combination of ruxolitinib and decitabine may be an effective therapeutic strategy for accelerated or blast phase MPN patients with JAK2V6m and TET2 mutations.