title: 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.
authors.affiliation: 1 Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University , Shanghai, China .
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhang
authors.forename: Chuan
authors.initials: C
authors.lastname: Lv
authors.forename: Xue
authors.initials: X
authors.lastname: Yang
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Han
authors.forename: Shuili
authors.initials: S
authors.lastname: Zhang
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Zong
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Qiudong
authors.initials: Q
authors.lastname: Zhao
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Fenghai
authors.initials: F
authors.lastname: Yu
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Lixin
authors.initials: L
authors.lastname: Wei
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D003345:Corticosterone / Q000502:physiology*; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D008810:Mice, Inbred C57BL; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; C515256:Cxcl12 protein, mouse; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D002251:Carbon Tetrachloride; D003345:Corticosterone