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Corticosterone mediates the inhibitory effect of restraint stress on the migration of mesenchymal stem cell to carbon tetrachloride-induced fibrotic liver by downregulating CXCR4/7 expression.

ABSTRACT: Recent studies have revealed that mesenchymal stem cells (MSCs) have a great potential in therapeutic applications. The low efficiency of MSC recruitment and homing to sites of diseased organ tissue, however, remains a major hurdle in their application for treatment of diseases. Stress is commonly associated with various diseases. At the present time, little information is available about the effect of stress on MSC function. Here, we employed a carbon tetrachloride (CCl4)-induced mouse liver fibrosis model to investigate whether constraint stress affects the migration of MSCs to fibrotic liver. MSC homing to the fibrotic liver was significantly inhibited in mice with restraint stress. Restraint stress induced an elevation of corticosterone level in the serum. Blocking glucocorticoid signaling with either corticosterone-synthesis inhibitor metyrapone (MET) or glucocorticoid receptor antagonist RU486 attenuated restraint stress-induced inhibition of MSCs migration. The serum concentration of stromal cell-derived factor-1 (SDF-1) increased in mice treated with CCl4. Restraint stress had no influence on expression of SDF-1 and hepatocyte growth factor (HGF) in the fibrotic liver. Culture with the serum of CCl4-treated mice or SDF-1 promoted MSC migration, which was suppressed by corticosterone. Exposure of MSCs to corticosterone decreased their expression of C-X-C chemokine receptor type 4 (CXCR4) and C-X-C chemokine receptor type 7 (CXCR7). These results demonstrate that the inhibitory effect of corticosterone on MSC migration might be mediated via decreasing the expression of CXCR4 and CXCR7 in MSCs. Interventions targeting the interaction between corticosterone and its receptor improve migration and homing of MSCs in hosts receiving transplantation of these cells.

SUBMITTER: Zhang S

PROVIDER: S-EPMC4333322 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Corticosterone mediates the inhibitory effect of restraint stress on the migration of mesenchymal stem cell to carbon tetrachloride-induced fibrotic liver by downregulating CXCR4/7 expression.

Zhang Shanshan S Lv Chuan C Yang Xue X Han Zhipeng Z Zhang Shuili S Zhang Jianwei J Zong Chen C Gao Lu L Li Li L Zhao Qiudong Q Li Rong R Yang Yang Y Yu Fenghai F Li Xiaoning X Zhang Ping P Wei Lixin L

Stem cells and development 20141111 5

Recent studies have revealed that mesenchymal stem cells (MSCs) have a great potential in therapeutic applications. The low efficiency of MSC recruitment and homing to sites of diseased organ tissue, however, remains a major hurdle in their application for treatment of diseases. Stress is commonly associated with various diseases. At the present time, little information is available about the effect of stress on MSC function. Here, we employed a carbon tetrachloride (CCl4)-induced mouse liver fi ...[more]

PMID: 25268050

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Project description:Peroxisome proliferator-activated receptor (PPAR) beta/delta-null mice exhibit exacerbated hepatotoxicity in response to administration of carbon tetrachloride (CCl(4)). To determine whether ligand activation of the receptor protects against chemical toxicity in the liver, wild-type and PPARbeta/delta-null mice were administered CCl(4) with or without coadministration of the highly specific PPARbeta/delta ligand GW0742. Biomarkers of liver toxicity, including serum alanine aminotransferase (ALT) and hepatic tumor necrosis factor (TNF) alpha mRNA, were significantly higher in CCl(4)-treated PPARbeta/delta-null mice compared to wild-type mice. Hepatic expression of TNF-like weak inducer of apoptosis receptor (TWEAKr) and S100 calcium-binding protein A6 (S100A6/calcyclin), genes involved in nuclear factor kappa B signaling, was higher in the CCl(4)-treated PPARbeta/delta-null mice compared to wild-type mice. GW0742 treatment resulted in reduced serum ALT concentration and lower expression of CCl(4)-induced TNF-alpha, S100A6, monocyte chemoattractant protein-1 (MCP1), and TWEAKr in wild-type mice, and these effects were not observed in PPARbeta/delta-null mice. Expression of TNF-alpha was higher in PPARbeta/delta-null primary hepatocytes in response to interleukin-1beta treatment compared to wild-type hepatocytes, but GW0742 did not significantly modulate TNF-alpha expression in hepatocytes from either genotype. While PPARbeta/delta-null hepatic stellate exhibited higher rates of proliferation compared to wild-type cells, GW0742 did not affect alpha-smooth muscle actin expression in these cells. Combined, these findings demonstrate that ligand activation of PPARbeta/delta protects against chemically induced hepatotoxicity by downregulating expression of proinflammatory genes. Hepatocytes and hepatic stellate cells do not appear to directly mediate the inhibitory effects of ligand activation of PPARbeta/delta in liver, suggesting the involvement of paracrine and autocrine events mediated by hepatic cells.

Dataset Information

Corticosterone mediates the inhibitory effect of restraint stress on the migration of mesenchymal stem cell to carbon tetrachloride-induced fibrotic liver by downregulating CXCR4/7 expression.

Publications

Corticosterone mediates the inhibitory effect of restraint stress on the migration of mesenchymal stem cell to carbon tetrachloride-induced fibrotic liver by downregulating CXCR4/7 expression.

Similar Datasets

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