Tissue transglutaminase-mediated cross-linking of extracellular matrix proteins for regulating keratinocytes and fibroblasts in matrix remodelling and wound healing

Skin repair remains a major clinical challenge because wound healing is a complex and tightly regulated process. It involves coordinated cell migration, proliferation, inflammation, and angiogenesis that collectively determine post-injury recovery. Central to this process, the extracellular matrix (ECM) functions as a dynamic and instructive microenvironment, governing cellular responses through integrated biomechanical and biochemical signaling to maintain tissue homeostasis and wound repair. However, despite advances in biomaterial design, current regenerative approaches often fail to recapitulate this level of ECM complexity, resulting in suboptimal and variable healing outcomes. Tissue transglutaminase (TG2) has emerged as a key enzymatic crosslinker that stabilizes the ECM by forming covalent bonds between ECM proteins, thereby enhancing matrix integrity. Moreover, it regulates several cellular signaling pathways, including Syndecan-4, TGF-β, integrin-mediated, and Wnt/β-catenin pathways, essential for coordinated wound repair and tissue remodeling. This review highlights the central role of TG2 in wound repair, emphasizing its functions in inflammation, angiogenesis, and ECM remodeling, as well as its regulation of fibroblast and keratinocyte re-epithelialization. It also summarizes key signaling pathways, crosslinking domains, and interaction sites of TG2 relevant to healing. In addition, we discuss recent advances in microbial transglutaminase (mTG)- and tissue transglutaminase (TG2)- crosslinked biomaterials and mTG/TG2-mediated 3D-printed/bioprinted constructs for wound healing, along with future prospects in this emerging field.