Angptl4 is upregulated by microenvironmental factors during the wound healing process and promotes epidermal stem cell proliferation via PRL8a6

Angiopoietin-like 4 (ANGPTL4) expression is increased in wound tissue and contributes to wound healing. However, the underlying mechanisms are not fully understood. Here, we demonstrate that ANGPTL4 expression is significantly increased in epidermal stem cells (EpSCs) in the periwound epidermis during wound healing in mice. Increased Angptl4 expression is positively correlated with increased expressions of tumor growth factor-α, interleukin-1β, epidermal growth factor, nerve growth factor, fibroblast growth factor 7, and transforming growth factor-β1. Each of these molecules induces Angptl4 expression in mouse EpSCs. RNA sequencing of EpSCs derived from wild-type and Angptl4 knockout (Angptl4 ^-/-) mice reveals altered expressions of genes involved in the cell cycle and cell proliferation in Angptl4 ^-/- EpSCs, including a decrease in cyclin E2/A2/B1 and cyclin-dependent kinase 1 ( <i>Cdk1</i>) expression; an increase in Cdk inhibitor 2a ( <i>Cdkn2a</i>) and <i>Cdkn2b</i> expression; and a decrease in the prolactin (PRL) family members <i>Prl2a1</i>, <i>Prl8a1</i>, <i>Prl8a9</i>, and <i>Prl8a6</i>. Mechanistic studies reveal that ANGPTL4 stimulates EpSC proliferation via PRL8a6-mediated upregulation of cyclins A2/E2/B1 and Cdk1, downregulation of Cdkn2a, and acceleration of cell cycle progression from the G1 to the S and G2 phases. <i>In vivo</i> studies demonstrate that <i>Prl8a6</i> mRNA is upregulated by ANGPTL4 in mouse periwound tissue during skin wound healing. Knockdown of <i>Angptl4</i> or <i>Prl8a6</i> in periwound skin tissue impairs EpSC proliferation and delays wound re-epithelialization. In conclusion, our study demonstrates that, after skin injury, elevated levels of proinflammatory cytokines and growth factors in periwound tissue stimulate <i>Angptl4</i> expression in EpSCs and that ANGPTL4 promotes EpSC proliferation by increasing Prl8a6 expression, thereby accelerating wound re-epithelialization.