RT Journal Article
SR Electronic
T1 The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaai8524
DO 10.1126/scitranslmed.aai8524
VO 10
IS 432
A1 Kou, Xiaoxing
A1 Xu, Xingtian
A1 Chen, Chider
A1 Sanmillan, Maria Laura
A1 Cai, Tao
A1 Zhou, Yanheng
A1 Giraudo, Claudio
A1 Le, Anh
A1 Shi, Songtao
YR 2018
UL http://stm.sciencemag.org/content/10/432/eaai8524.abstract
AB 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.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.