Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0065-6) contains supplementary material, which is available to authorized users.
Highlights
Human mesenchymal stem cells 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
Human aortic endothelial cells secreted endothelin-1 to regulate human mesenchymal stem cell activities We first used hMSC/human aortic endothelial cell (HAEC) co-culture to investigate the effects of paracrine factors on hMSCs (Figure 1A) and hMSCs without HAEC as control culture
The cell number of hMSCs co-cultured with HAECs was higher than that of control hMSCs at day 8 (Figure 1C), suggesting that HAECs are able to increase proliferation of hMSCs. qRTPCR analysis of potency- and lineage-related markers showed that among cells from all three donors, hMSCs in co-culture expressed higher mRNA levels of lineagerelated transcription factors core-binding factor subunit alpha-1 (CBFA1), sex determining region Y-box 9 (SOX9), and peroxisome proliferator-activated receptor gamma 2 (PPARG2) than control hMSCs, while the expression levels of OCT3/ 4 and NANOG were comparable between co-cultured and control hMSCs (Figure 1D)
Summary
Human 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. Human mesenchymal stem cells (hMSCs) are multipotent and capable of self-renewal [1,2,3] They can be isolated from various adult and fetal tissues [4,5,6], and can be induced into osteo-, chondro-, or adipo-lineage cells in vitro and in vivo [7]. With these features, hMSCs hold great potential for regenerative medicine applications. Researchers have reported that hMSCs isolated from bone marrow express CD146, a surface marker of pericytes [15,16] These reports concordantly indicate that hMSCs reside in a perivascular niche of the body.
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