Regulation Of Epidermal Differentiation

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

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Abstract

Epidermis has been used as an excellent model to study the process of cellular differentiation because the cells form a stratified structure during development, and each stratum is easily identified by morphology and expression of specific markers. The process entails the outward movement of the proliferative basal cells that are adjacent to the basement membrane toward the surface of the skin. Our research efforts have focused on characterizing the regulation and function of the DLX3 homeobox transcription factor with essential roles in development. We have shown that DLX3 modulates the cell cycle progression during epidermal differentiation and a DLX3-dependent network modulates epidermal hyperplasia and squamous tumorigenesis. By integrating genetic and transcriptomic approaches, we demonstrated that DLX3 operates through a p53-regulated network. In contrast, DLX3 loss promotes a mitogenic phenotype associated with constitutive activation of ERK and STAT3. DLX3 expression is lost in human skin cancers and is extinguished during progression of experimentally induced mouse squamous cell carcinoma (SCC). Furthermore, we showed that loss of DLX3 tumor suppressive function promotes progression of SCC through the EGFR-ERBB2 pathway. These results establish DLX3 is a modulator of skin carcinogenesis. On studies of wound resolution, we performed a unique comparative analysis between human oral and cutaneous wound healing using paired and sequential biopsies during the repair process. Using molecular profiling, we determined that wound-activated transcriptional networks are present at a basal state in the oral mucosa, priming the epithelium for wound repair. We showed that oral mucosal wound-related networks control epithelial cell differentiation and regulate inflammatory responses, highlighting fundamental global mechanisms of repair and inflammatory responses in humans. The paired comparative analysis allowed for the identification of differentially expressed SOX2 and PITX1 transcriptional regulators in oral versus skin keratinocytes, conferring a unique identity to oral keratinocytes. We showed that SOX2 and PITX1 transcriptional function has the potential to reprogram skin keratinocytes to increase cell migration and improve wound resolution in vivo. In recent findings we showed that major transcriptional networks which promote activation and survival of immune cells are deregulated in diabetic foot ulcers (DFUs), resulting in decreased activation of neutrophils and macrophages and overall poorly controlled inflammatory response. We identified transcription factors FOXM1 and STAT3, which function to activate and promote survival of immune cells, to be inhibited in DFUs. We show that inhibition of FOXM1 resulted in delayed wound healing and decreased neutrophil and macrophage recruitment in diabetic wounds in vivo. More recently, we determined that TREM1 promoted the recruitment of FOXM1+ neutrophils and promoted wound healing in vivo. Activation of TREM1 promoted FOXM1+ neutrophil recruitment, decreased neutrophil extracellular traps (NETs) and enhanced diabetic wound healing in vivo, demonstrating a novel pathway for regulating NET formation in diabetic wounds. Moreover, we found that TREM1 expression correlated with clinical healing outcomes of DFUs. Our findings highlight the clinical relevance of TREM1 and point to the FOXM1 pathway as a novel regulator of NET formation during diabetic wound healing, revealing new therapeutic strategies to promote healing in DFUs. Our data provide insights into therapeutic targeting of chronic non-healing wounds based on greater understanding of the biology of healing in human mucosal and cutaneous environments.