Thrombospondin-4 Is a Soluble Dermal Inflammatory Signal That Selectively Promotes Fibroblast Migration and Keratinocyte Proliferation for Skin Regeneration and Wound Healing

Mariliis Klaas,Külli Kingo,Esko Kankuri,Claudia Griselda Cárdenas-León,Heli Lagus,Kristina Mäemets-Allas,Elizabeth Heinmäe,Mart Eller,Terje Arak,Viljar Jaks

doi:10.3389/fcell.2021.745637

Abstract

Thrombospondin-4 (THBS4) is a non-structural extracellular matrix molecule associated with tissue regeneration and a variety of pathological processes characterized by increased cell proliferation and migration. However, the mechanisms of how THBS4 regulates cell behavior as well as the pathways contributing to its effects have remained largely unexplored. In the present study we investigated the role of THBS4 in skin regeneration both in vitro and in vivo. We found that THBS4 expression was upregulated in the dermal compartment of healing skin wounds in humans as well as in mice. Application of recombinant THBS4 protein promoted cutaneous wound healing in mice and selectively stimulated migration of primary fibroblasts as well as proliferation of keratinocytes in vitro. By using a combined proteotranscriptomic pathway analysis approach we discovered that β-catenin acted as a hub for THBS4-dependent cell signaling and likely plays a key role in promoting its downstream effects. Our results suggest that THBS4 is an important contributor to wound healing and its incorporation into novel wound healing therapies may be a promising strategy for treatment of cutaneous wounds.

Highlights

Cutaneous wound healing is a multifactorial process which involves both dermal and epidermal components that have important roles in restoring the full integrity of skin (Eming et al, 2014; Rousselle et al, 2019)
In this work we demonstrated that THBS4 was an important contributor to cutaneous wound healing by stimulation of fibroblast migration at least in part via activation of β-catenindependent signaling pathways
As a proof of principle, we showed that the application of recombinant THBS4 directly to the wound area increased significantly cutaneous wound healing in a mouse full-thickness splinted wound model

Summary

Introduction

Cutaneous wound healing is a multifactorial process which involves both dermal and epidermal components that have important roles in restoring the full integrity of skin (Eming et al, 2014; Rousselle et al, 2019). The progressing steps of wound repair involve skin-resident cells and circulating blood cells, controlled layers of cell-to-cell signaling and secretion of soluble factors and extracellular matrix (ECM) components that all play crucial roles in skin regeneration. Matricellular proteins are ECM components that do not possess a structural role but regulate tissue homeostasis and wound healing. Several matricellular components such as thrombospondins, osteopontin, and tenascin are expressed at higher levels in healing wounds (Bornstein and Sage, 2002)

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