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Bone marrow-derived mesenchymal stem cells differentiate to hepatic myofibroblasts by transforming growth factor-β1 via sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis.
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- Author(s): Yang L;Yang L; Chang N; Liu X; Han Z; Zhu T; Li C; Yang L; Li L
- Source:
The American journal of pathology [Am J Pathol] 2012 Jul; Vol. 181 (1), pp. 85-97. Date of Electronic Publication: 2012 May 17.
- Publication Type:
Journal Article; Research Support, Non-U.S. Gov't
- Language:
English
- Additional Information
- Source:
Publisher: Elsevier Country of Publication: United States NLM ID: 0370502 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-2191 (Electronic) Linking ISSN: 00029440 NLM ISO Abbreviation: Am J Pathol Subsets: MEDLINE
- Publication Information:
Publication: 2011-: New York : Elsevier
Original Publication: Philadelphia [etc.] American Assn. of Pathologists [etc.]
- Subject Terms:
- Abstract:
Sphingosine kinase (SphK) is involved in numerous biological processes, including cell growth, proliferation, and differentiation. However, whether SphK participates in the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) to myofibroblasts has been unknown. In a carbon tetrachloride-treated mouse model, SphK1 was expressed in BMSCs in damaged liver. Furthermore, mRNA expression of both SphK1 and transforming growth factor β1 (TGF-β1) was significantly increased after liver injury, with a positive correlation between them. The SphK inhibitor SKI significantly blocked BMSC differentiation to myofibroblasts during liver injury (the proportion of BMSC-derived myofibroblasts decreased markedly, compared with no SKI treatment) and attenuated the extent of liver fibrosis. Using primary mouse BMSCs, we demonstrated that TGF-β1 induced BMSC differentiation to myofibroblasts, accompanied by the up-regulation of SphK1 and modulation of sphingosine 1-phosphate (S1P) receptor (S1PR) expression. Notably, pharmacological or siRNA-mediated inhibition of SphK1 abrogated the prodifferentiating effect of TGF-β1. Moreover, using either S1PR subtype-specific antagonists or specific siRNAs, we found that the prodifferentiating effect of TGF-β1 was mediated by S1PR(1) and S1PR(3). These data suggest that SphK1 activation by TGF-β1 leads to differentiation of BMSCs to myofibroblasts mediated by S1PR(1) and S1PR(3) up-regulation, thus providing new information on the mechanisms by which TGF-β1 gives rise to fibrosis and opening new perspectives for pharmacological treatment of liver fibrosis.
(Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Accession Number:
0 (Enzyme Inhibitors)
0 (RNA, Small Interfering)
0 (Receptors, Lysosphingolipid)
0 (Transforming Growth Factor beta1)
37758-47-7 (G(M1) Ganglioside)
CL2T97X0V0 (Carbon Tetrachloride)
EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
EC 2.7.1.- (sphingosine kinase)
- Publication Date:
Date Created: 20120522 Date Completed: 20121029 Latest Revision: 20181201
- Publication Date:
20240829
- Accession Number:
10.1016/j.ajpath.2012.03.014
- Accession Number:
22609227
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