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Simvastatin inhibits the adipogenesis of bone marrow?derived mesenchymal stem cells through the downregulation of chemerin/CMKLR1 signaling.

ABSTRACT: Simvastatin is effective in the treatment of osteoporosis, partly through the inhibition of the adipogenesis of bone?marrow derived mesenchymal stem cells (BMSCs). The present study focused on the mechanisms responsible for the inhibitory effects of simvastatin on adipogenesis and examined the effects of simvastatin on the expression of peroxisome proliferator?activated receptor ? (PPAR?), chemerin, chemokine?like receptor 1 (CMKLR1), G protein?coupled receptor 1 (GPR1) and the adipocyte marker gene, adiponectin. BMSCs were isolated from 4?week?old female Sprague?Dawley (SD) rats, and adipogenesis was measured by the absorbance values at 490 nm of Oil Red O dye. The expression of each gene was evaluated by western blot analysis or reverse transcription?quantitative PCR (RT?qPCR). The expression of chemerin increased during adipogenesis, while CMKLR1 exhibited a trend towards a decreased expression. On days 7 and 14, the simvastatin?treated cells exhibited a downregulated expression of chemerin, whereas the upregulated expression of its receptor, CMKLR1 was observed. The results also revealed that CMKLR1 is required for adipogenesis and the simvastatin?mediated inhibitory effect on adipogenesis. Simvastatin regulated adipogenesis by negatively modulating chemerin?CMKLR1 signaling. Importantly, simvastatin stimulation inhibited the upregulation of PPAR? and PPAR??mediated chemerin expression to prevent adipogenesis. Treatment with the PPAR? agonist, rosiglitazone, partially reversed the negative regulatory effects of simvastatin. On the whole, the findings of the present study demonstrate that simvastatin inhibits the adipogenesis of BMSCs through the downregulation of PPAR? and subsequently prevents the PPAR??mediated induction of chemerin/CMKLR1 signaling.

SUBMITTER: Guo Y

PROVIDER: S-EPMC7307816 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Simvastatin inhibits the adipogenesis of bone marrow‑derived mesenchymal stem cells through the downregulation of chemerin/CMKLR1 signaling.

Guo Yao Y Huo Jianzhong J Wu Dou D Hao Haihu H Ji Xinghua X Zhao Enzhe E Nie Boyuan B Liu Qiang Q

International journal of molecular medicine 20200518 2

Simvastatin is effective in the treatment of osteoporosis, partly through the inhibition of the adipogenesis of bone‑marrow derived mesenchymal stem cells (BMSCs). The present study focused on the mechanisms responsible for the inhibitory effects of simvastatin on adipogenesis and examined the effects of simvastatin on the expression of peroxisome proliferator‑activated receptor γ (PPARγ), chemerin, chemokine‑like receptor 1 (CMKLR1), G protein‑coupled receptor 1 (GPR1) and the adipocyte marker ...[more]

PMID: 32468037

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Project description:UnlabelledMesenchymal stem cells (MSCs) can differentiate into multiple lineages through guidance from the biophysical and biochemical properties of the extracellular matrix. In this work we conduct a combinatorial study of matrix properties that influence adipogenesis and neurogenesis including: adhesion proteins, stiffness, and cell geometry, for mesenchymal stem cells derived from adipose tissue (AT-MSCs) and bone marrow (BM-MSCs). We uncover distinct differences in integrin expression, the magnitude of traction stress, and lineage specification to adipocytes and neuron-like cells between cell sources. In the absence of media supplements, adipogenesis in AT-MSCs is not significantly influenced by matrix properties, while the converse is true in BM-MSCs. Both cell types show changes in the expression of neurogenesis markers as matrix cues are varied. When cultured on laminin conjugated microislands of the same adhesive area, BM-MSCs display elevated adipogenesis markers, while AT-MSCs display elevated neurogenesis markers; integrin analysis suggests neurogenesis in AT-MSCs is guided by adhesion through integrin αvβ3. Overall, the properties of the extracellular matrix guides MSC adhesion and lineage specification to different degrees and outcomes, in spite of their similarities in general characteristics. This work will help guide the selection of MSCs and matrix components for applications where high fidelity of differentiation outcome is desired.Statement of significanceMesenchymal stem cells (MSCs) are an attractive cell type for stem cell therapies; however, in order for these cells to be useful in medicine, we need to understand how they respond to the physical and chemical environments of tissue. Here, we explore how two promising sources of MSCs-those derived from bone marrow and from adipose tissue-respond to the compliance and composition of tissue using model extracellular matrices. Our results demonstrate a source-specific propensity to undergo adipogenesis and neurogenesis, and uncover a role for adhesion, and the degree of traction force exerted on the substrate in guiding these lineage outcomes.

Project description:The microenvironment plays a vital role in both the maintenance of stem cells in their undifferentiated state (niche) and their differentiation after homing into new locations outside this niche. Contrary to conventional in-vitro culture practices, the in-vivo stem cell microenvironment is physiologically crowded. We demonstrate here that re-introducing macromolecular crowding (MMC) at biologically relevant fractional volume occupancy during chemically induced adipogenesis substantially enhances the adipogenic differentiation response of human bone marrow-derived mesenchymal stem cells (MSCs). Both early and late adipogenic markers were significantly up-regulated and cells accumulated 25-40% more lipid content under MMC relative to standard induction cocktails. MMC significantly enhanced deposition of extracellular matrix (ECM), notably collagen IV and perlecan, a heparan sulfate proteoglycan. As a novel observation, MMC also increased the presence of matrix metalloproteinase -2 in the deposited ECM, which was concomitant with geometrical ECM remodeling typical of adipogenesis. This suggested a microenvironment that was richer in both matrix components and associated ligands and was conducive to adipocyte maturation. This assumption was confirmed by seeding undifferentiated MSCs on decellularized ECM deposited by adipogenically differentiated MSCs, Adipo-ECM. On Adipo-ECM generated under crowding, MSCs differentiated much faster under a classical differentiation protocol. This was evidenced throughout the induction time course, by a significant up-regulation of both early and late adipogenic markers and a 60% higher lipid content on MMC-generated Adipo-ECM in comparison to standard induction on tissue culture plastic. This suggests that MMC helps build and endow the nascent microenvironment with adipogenic cues. Therefore, MMC initiates a positive feedback loop between cells and their microenvironment as soon as progenitor cells are empowered to build and shape it, and, in turn, are informed by it to respond by attaining a stable differentiated phenotype if so induced. This work sheds new light on the utility of MMC to tune the microenvironment to augment the generation of adipose tissue from differentiating human MSCs.

Dataset Information

Simvastatin inhibits the adipogenesis of bone marrow?derived mesenchymal stem cells through the downregulation of chemerin/CMKLR1 signaling.

Publications

Simvastatin inhibits the adipogenesis of bone marrow‑derived mesenchymal stem cells through the downregulation of chemerin/CMKLR1 signaling.

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