Stimulation with THBS4 activates pathways that regulate proliferation, migration and inflammation in primary human keratinocytes

As in other mammalian tissues, the extracellular matrix (ECM) of skin functions as mechanical support and regulative environment that guides the behavior of the cells. ECM is a gel-like structure that is primarily composed of structural and nonstructural proteins. While the content of structural proteins is stable, the level of nonstructural ECM proteins, such as thrombospondin-4 (THBS4), is dynamically regulated. In a previous work we demonstrated that THBS4 stimulated cutaneous wound healing. In this work we discovered that in addition to proliferation, THBS4 stimulated the migration of primary keratinocytes in 3D. By using a proteotransciptomic approach we found that stimulation of keratinocytes with THBS4 regulated the activity of signaling pathways linked to proliferation, migration, inflammation and differentiation. Interestingly, some of the regulated genes (eg IL37, TSLP) have been associated with the pathogenesis of atopic dermatitis (AD). We concluded that THBS4 is a promising candidate for novel wound healing therapies and suggest that there is a potential convergence of pathways that stimulate cutaneous wound healing with those active in the pathogenesis of inflammatory skin diseases.(c) 2022 Published by Elsevier Inc.

Automated summary

Similar to other mammalian tissues, the extracellular matrix (ECM) in the skin serves as a supportive and regulatory environment for cell behavior. It is primarily composed of structural and nonstructural proteins, with the latter, including thrombospondin-4 (THBS4), being dynamically regulated. Previous research showed that THBS4 promotes cutaneous wound healing, and this study reveals its additional role in stimulating the migration of primary keratinocytes in a 3D environment. Through proteotranscriptomic analysis, it was found that THBS4 regulates signaling pathways associated with proliferation, migration, inflammation, and differentiation in keratinocytes, some of which are implicated in the development of atopic dermatitis (AD). Overall, THBS4 shows promise as a candidate for novel wound healing therapies, and there may be overlap between the pathways involved in cutaneous wound healing and those active in inflammatory skin diseases.