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The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing.

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-? (TNF-?) serves as an activator to up-regulate Fas and Fap-1 expression via the nuclear factor ?B 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.

SUBMITTER: Kou X

PROVIDER: S-EPMC6310133 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing.

Kou Xiaoxing X Xu Xingtian X Chen Chider C Sanmillan Maria Laura ML Cai Tao T Zhou Yanheng Y Giraudo Claudio C Le Anh A Shi Songtao S

Science translational medicine 20180301 432

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 <i>N</i>-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE)-mediated membrane fusion mechanism to rele ...[more]

PMID: 29540618

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Project description:BackgroundMedication-related osteonecrosis of the jaw (MRONJ) is a serious debilitating disease caused by anti-resorption and anti-angiogenesis drugs, significantly affecting patients' quality of life. Recent studies suggested that primary gingival wound healing may effectively prevent the development of MRONJ. This study aimed to evaluate the effects of low-level light therapy (LLLT) on promoting gingival wound healing in extraction sockets of MRONJ-like mice and preventing the occurrence of MRONJ. Furthermore, we explored underlying mechanisms.MethodsMice were randomly divided into the Ctrl, Zol, and Zol + LLLT groups. Administration of zoledronate and tooth extraction of bilateral maxillary second molars were used to build the MRONJ model, and LLLT was locally administered into the tooth sockets to examine the effect of LLLT. Next, to explore the function of IL-1RA, we performed LLLT with interleukin-1 receptor antagonist (IL-1RA) neutralizing antibody (named Zol + LLLT + IL-1RA NAb group) or negative control antibodies for tooth extraction in subsequent rescue animal experiments. Stereoscope observations, micro-computed tomography, and histological examination were conducted to evaluate gingival wound healing and bone regeneration in tooth sockets. The effects of LLLT on the migration capacities of zoledronate-treated epithelial cells were assessed in vitro.ResultsLLLT promoted primary gingival wound healing without exposed necrotic bone. Micro-computed tomography results showed higher bone volume and mineral density of the tooth sockets after LLLT. Histology analysis showed complete gingival coverage, obvious bone regeneration, and reduced soft tissue inflammation, with down-regulated pro-inflammation cytokines, like interleukin-1 beta (IL-1β) and tumor necrosis factor-α (TNF-α), and up-regulated IL-1RA expression in the gingival tissue in the LLLT group. The rescue assay further showed that the effects of LLLT promoting gingival wound healing and preventing MRONJ might be partially abolished by IL-1RA neutralizing antibodies. In vitro studies demonstrated that LLLT accelerated zoledronate-treated epithelial cell migration.ConclusionsLLLT might promote primary gingival wound healing and contribute to subsequent bone regeneration of the tooth extractions in MRONJ-like lesions via IL-1RA-mediated pro-inflammation signaling suppression.

Dataset Information

The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing.

Publications

The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing.

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