Abstract
Olfactomedin-4 (OLFM4) is an olfactomedin-domain-containing glycoprotein, which regulates cell adhesion, proliferation, gastrointestinal inflammation, innate immunity and cancer metastasis. In the present study we investigated its role in skin regeneration. We found that OLFM4 expression is transiently upregulated in the proliferative phase of cutaneous wound healing in humans as well as in mice. Moreover, a significant increase in OLFM4 expression was detected in the skin of lesional psoriasis, a chronic inflammatory disease characterized by keratinocyte hyperproliferation. In vitro experiments demonstrated that OLFM4 selectively stimulated keratinocyte proliferation and increased both keratinocyte and fibroblast migration. Using proteotranscriptomic pathway analysis we revealed that transcription factors POU5F1/OCT4 and ESR1 acted as hubs for OLFM4-induced signalling in keratinocytes. In vivo experiments utilizing mouse splinted full-thickness cutaneous wound healing model showed that application of recombinant OLFM4 protein can significantly improve wound healing efficacy. Taken together, our results suggest that OLFM4 acts as a transiently upregulated inflammatory signal that promotes wound healing by regulating both dermal and epidermal cell compartments of the skin.
Highlights
Mammalian skin is designed to act as a barrier to the environment, providing mechanical, ultraviolet light and chemical protection, preventing pathogen invasion and microbial growth, participating in thermal regulation, fluid homeostasis and contributing to the production of vital hormones
No significant changes in Olfactomedin 4 (OLFM4) protein levels were detected at later timepoints (14 days and 21 days), indicating that OLFM4 is transiently increased in the dermal compartment during the proliferative phase of wound healing (Fig. 1C)
In this study we investigated for the first time the role of OLFM4 in mammalian cutaneous wound healing
Summary
Mammalian skin is designed to act as a barrier to the environment, providing mechanical, ultraviolet light and chemical protection, preventing pathogen invasion and microbial growth, participating in thermal regulation, fluid homeostasis and contributing to the production of vital hormones. Wound healing involves a series of tightly orchestrated spatially and temporally overlapping processes including blood coagulation, inflammation, keratinocyte migration and proliferation as well as tissue and extracellular matrix (ECM) remodelling [1]. Infection and inflammation have been shown to increase the expression of OLFM4, and its high expression has been reported in gastric biopsies of patients with Helicobacter pylori infection and inflammatory bowel disease [15]. These results indicate a dynamic role for OLFM4 in tissue homeostasis and suggest that OLFM4 has time- and concentration-dependent roles in inflammatory pathologies [16]
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