Hyaluronan Synthase 2 (has2) Regulation Of Inflammation In Dermal Fibroblasts During Wound Healing
Mason Bartels, Yucel Akgul.
UT Southwestern Medical Center, Dallas, TX, USA.
BACKGROUND: Impaired wound-healing is a severe complication of diabetes, which affects about 9.3% of the US population. Some of the major environmental factors in the pathologically complex diabetic wounds are correlated with chronic inflammation, hypoxia, and elevated glucose levels. The molecular mechanisms by which these factors lead to poor wound healing, however, are not well understood. The current study evaluates the intracellular (hexosamine pathway) and extracellular (TLR pathway) mechanisms by which Has2 and its hyaluronan production participate in inflammation during cutaneous wound healing. METHODS: To understand the contribution of dermal Has2 function to wound healing, conditional Has2 knockout in the mouse dermis was achieved by crossing Hyaluronan synthase 2 (Has2/loxP) with fibroblast specific Dlk1-CreER. The ability of Has2 to serve as a regulator of inflammation were also tested using diabetic foot ulcer waste tissues and cultured human primary dermal fibroblasts that are non-diabetic and diabetic. RESULTS: Human diabetic foot ulcer characterized by dysregulated hyaluronan expression with increased immune cell infiltration and inflammatory activity. Diabetic fibroblasts in culture expressed higher baseline immune gene expression compared with non-diabetic cells. Both intracellular and extracellular hyaluronan were critical for regulation of inflammatory factors including IL6 and IL8 in primary human fibroblasts. Has2 loss in the dermal fibroblasts of transgenic mouse model resulted in impaired wound healing with increased inflammation and O-GlcNAcylation. CONCLUSIONS our studies suggest that Has2 driven hyaluronan production plays a critical role in both granulation tissue formation and inflammation.
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