Hyaluronan Synthase 2 Knock Down in Epidermis Alter Wound Healing and Hair Follicle Development
Mason Bartels, BS, Yucel Akgul, MD, PhD.
University of Texas Southwestern Medical Center, Dallas, TX, USA.
PURPOSE: Impaired wound healing is a serious complication and impacts patient’s quality of life adversely. Among extracellular matrix (ECM) molecules, hyaluronan (HA) has been suggested to play a critical role in all phases of wound healing as it modulates cell behavior including adhesion, migration, proliferation, metabolism and differentiation. HA is produced by 3 distinct hyaluronan synthesis (Has) and exists in varying sizes. It is widely accepted that large molecular weight HA is involved in structural and anti-inflammatory functions, whereas small molecular weight HA is angiogenetic and pro-inflammatory. METHODS: To evaluate the cell specific functions of HA in wound healing, human primary cell culture and transgenic mice that lack epidermal Has2 were utilized. Transgenic mice were generated by crossing Keratin-14 CreER with Has2flox/flox and tamoxifen injection (HA KO). Gene expression and histological evaluation were utilized in this study. For cell culture studies, human dermal fibroblasts and keratinocytes were isolated from the waste skin tissue of patients undergoing plastic surgeries. RESULTS: Among 3 hyaluronan synthesis, Has3 was responsible for majority of the HA production in differentiated keratinocytes. In contrast, Has2 gene expression and HA production were much higher in epidermal stem cells suggesting that Has2 has a critical role in stem cell function. Interestingly, both epidermal stem cells (first 2 passage after dermal keratinocyte isolation) were highly sensitive to immune stimulation following TLR agonist treatment, however HA production, Has2 expression and immune response decreased with increasing passage number as keratinocytes mature. Furthermore, immune response to TLR agonists was blocked by Has2/Has3 blocking reagent suggesting that HA may have a role in chronic inflammation associated with impaired wound healing like diabetic ulcers. Wound closure especially reepithelization following wounding surgery was not effected in the HA KO mice compare to wild type. However, histological evaluation suggested that the wound repair was much slower in HA KO mice compare to their wild type siblings. Particularly, higher collagen expression in the granulation tissue and epidermis. In addition, HA expression in the granulation tissue of HA KO wounds were much lower compare to wild type. Moreover, hair follicle development was altered in the HA KO mice with larger gland development compare to wild type. CONCLUSION: Collectively these studies provide unexpected results regarding the roles of HA in the epidermal cells of wound healing. While HA secretion by Has2 in epidermal cells is not obligatory for reepithelization, it is critical for collagen matrix reorganization during wound healing.
Back to 2017 Program