Secreting cytokines to correct cuts
Wound healing is a multi-phase process encompassing inflammation, cell proliferation, and the deposition and remodeling of extracellular matrix. To understand the molecular signaling pathways contributing to this process, Kou et al. studied cytokine secretion during wound healing. They found that mesenchymal stem cells secrete extracellular vesicles via a caveolin-1–mediated exocytotic process and produce interleukin-1 receptor antagonist (IL-1RA) during gingival and cutaneous wound healing in mice. Treating wounds with recombinant IL-1RA or small extracellular vesicles expressing IL-1RA accelerated wound healing. This signaling pathway could be targeted to develop wound healing therapies.
Abstract
Mesenchymal stem cells (MSCs) are capable of secreting exosomes, extracellular vesicles, and cytokines to regulate cell and tissue homeostasis. However, it is unknown whether MSCs use a specific exocytotic fusion mechanism to secrete exosomes and cytokines. We show that Fas binds with Fas-associated phosphatase–1 (Fap-1) and caveolin-1 (Cav-1) to activate a common soluble N-ethylmaleimide–sensitive factor (NSF) attachment protein receptor (SNARE)–mediated membrane fusion mechanism to release small extracellular vesicles (sEVs) in MSCs. Moreover, we reveal that MSCs produce and secrete interleukin-1 receptor antagonist (IL-1RA) associated with sEVs to maintain rapid wound healing in the gingiva via the Fas/Fap-1/Cav-1 cascade. Tumor necrosis factor–α (TNF-α) serves as an activator to up-regulate Fas and Fap-1 expression via the nuclear factor κB pathway to promote IL-1RA release. This study identifies a previously unknown Fas/Fap-1/Cav-1 axis that regulates SNARE-mediated sEV and IL-1RA secretion in stem cells, which contributes to accelerated wound healing.
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