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Endothelin-1 reduces catabolic activity of human mesenchymal stem/stromal cells during chondro- and osteo-lineage differentiation.

ABSTRACT: Human mesenchymal stem/stromal cells (hMSCs) reside in a vascularized microenvironment and experience a host of blood vessel secretions, including endothelin-1 (ET1). Previously, our group has demonstrated improved induction of osteogenesis and chondrogenesis in hMSCs through an ET1-induced increase in production of anabolic factors. The current study explores effects of ET1 on catabolic factors secreted by hMSCs during chondrogenesis and osteogenesis. Cell proliferation and extracellular matrix (ECM) deposition were also explored. Our results demonstrated that ET1 reduced mRNA transcript levels of MMP2, MMP13, ADAMTS4, and ADAMTS5 in chondrogenic hMSCs, and MMP13 and ADAMTS5 in osteogenic hMSCs. Furthermore, ET1-treated chondrogenic and osteogenic hMSCs showed more intense stains for Alcian blue and Alizarin red S, respectively, than control cells. Immunocytochemical results demonstrated that the ET1-mediated reduction of MMP13 could be reversed through blocking ET1 induction. Overall, our findings indicate that hMSCs treated with ET1 during chondrogenic or osteogenic induction attenuate catabolic activities of the cell to reduce ECM degradation, suggesting that it may be beneficial to use ET1 to enhance hMSC differentiation and protect newly synthesized ECM from degradation.

SUBMITTER: Weishar R

PROVIDER: S-EPMC7385289 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionHuman mesenchymal stem cells (hMSCs) reside in a perivascular niche of the body, suggesting that they interact closely with vascular endothelial cells (ECs) through cell-cell interaction or paracrine signaling to maintain cell functions. Endothelin-1 (ET1) is a paracrine factor mainly secreted by ECs. We thus hypothesize that ECs can regulate cellular activities of hMSCs and direct their stem cell fate.MethodsWe investigated whether co-cultured human aortic endothelial cells (HAECs) were able to regulate expression of potency- and lineage-related markers in bone marrow-derived hMSCs. We further explored the regulatory effects of ET1 on cell proliferation, expression of surface antigens and pluripotency-related markers, and multilineage differentiation in hMSCs. Activation of the AKT signaling pathway in hMSCs was also analyzed to identify its mechanistic role in the ET1-induced regulation.ResultsCo-cultured HAECs enhanced expression of mesenchymal lineage-related markers in hMSCs. Treatment of ET receptor antagonist downregulated the increased expression of CBFA1 in hMSCs cultured with HAEC-conditioned medium. hMSCs treated with ET1 showed cell proliferation and expression of surface antigens, CD73, CD90, and CD105, comparable with those without ET1 treatment. ET1-treated hMSCs also expressed upregulated mRNA transcript levels of OCT3/4, NANOG, CBFA1 and SOX9. When induced for lineage-specific differentiation, hMSCs pre-treated with ET1 showed enhanced osteogenesis and chondrogenesis. However, adipogenic differentiation of hMSCs was not affected by ET1 pretreatment. We further showed that the ET1-induced regulation was mediated by activation of AKT signaling.ConclusionOur results demonstrate that ET1 secreted by HAECs can direct bone marrow-derived hMSCs for osteo- and chondro-lineage differentiation through activation of the AKT signaling pathway, suggesting that ET1 plays a crucial role in regulation of hMSC activity. Our findings may help understand how hMSCs interact with ECs in a perivascular niche.

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Endothelin-1 reduces catabolic activity of human mesenchymal stem/stromal cells during chondro- and osteo-lineage differentiation.

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