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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7
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pubmed:dateCreated |
2011-6-29
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pubmed:abstractText |
Hematopoietic stem cell (HSC) self-renewal is tightly regulated by a complex crosstalk between many cell-intrinsic regulators and a variety of extrinsic signals from the stem cell niche. In this study, we examined whether the p38 mitogen-activated protein kinase (p38) is one of the intrinsic regulators that can negatively regulate HSC self-renewal in vitro and whether inhibition of p38 activity with a small molecule inhibitor can promote HSC expansion ex vivo. The results from this study showed that sorted mouse bone marrow Lin(-)Sca1(+)c-kit(+) cells (LSK(+) cells) exhibited selective activation of p38 after culture in a serum-free medium supplemented with 100 ng/mL stem cell factor, thrombopoietin, and Flt3 ligand. The activation of p38 was associated with a significant reduction in HSCs and induction of apoptosis and cellular senescence in LSK(+) cells and their progeny. Addition of the specific p38 inhibitor SB203580 (SB, 5 ?M) to the culture inhibited the activation of p38 in LSK(+) cells, which led to increase in HSC self-renewal and ex vivo expansion as shown by the cobblestone area forming cell assay, competitive repopulation, and serial transplantation. The increase in HSC expansion is likely attributable to SB-mediated inhibition of HSC apoptosis and senescence and upregulation of HoxB4 and CXCR4. These findings suggest that p38 plays an important role in the regulation of HSC self-renewal in vitro and inhibition of p38 activation with a small molecule inhibitor may represent a novel approach to promote ex vivo expansion of HSCs.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/CXCR4 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Homeodomain Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Hoxb4 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Imidazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, CXCR4,
http://linkedlifedata.com/resource/pubmed/chemical/SB 203580,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/p38 Mitogen-Activated Protein...
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1557-8534
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
20
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1143-52
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pubmed:meshHeading |
pubmed-meshheading:21198398-Analysis of Variance,
pubmed-meshheading:21198398-Animals,
pubmed-meshheading:21198398-Apoptosis,
pubmed-meshheading:21198398-Cell Aging,
pubmed-meshheading:21198398-Cell Culture Techniques,
pubmed-meshheading:21198398-Cell Differentiation,
pubmed-meshheading:21198398-Cell Growth Processes,
pubmed-meshheading:21198398-Cell Proliferation,
pubmed-meshheading:21198398-Cell Transplantation,
pubmed-meshheading:21198398-Cells, Cultured,
pubmed-meshheading:21198398-Enzyme Activation,
pubmed-meshheading:21198398-Enzyme Inhibitors,
pubmed-meshheading:21198398-Flow Cytometry,
pubmed-meshheading:21198398-Hematopoietic Stem Cell Transplantation,
pubmed-meshheading:21198398-Hematopoietic Stem Cells,
pubmed-meshheading:21198398-Homeodomain Proteins,
pubmed-meshheading:21198398-Imidazoles,
pubmed-meshheading:21198398-Male,
pubmed-meshheading:21198398-Mice,
pubmed-meshheading:21198398-Mice, Inbred C57BL,
pubmed-meshheading:21198398-Microscopy, Fluorescence,
pubmed-meshheading:21198398-Phosphorylation,
pubmed-meshheading:21198398-Pyridines,
pubmed-meshheading:21198398-Receptors, CXCR4,
pubmed-meshheading:21198398-Transcription Factors,
pubmed-meshheading:21198398-Up-Regulation,
pubmed-meshheading:21198398-p38 Mitogen-Activated Protein Kinases
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pubmed:year |
2011
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pubmed:articleTitle |
Inhibition of p38 mitogen-activated protein kinase promotes ex vivo hematopoietic stem cell expansion.
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pubmed:affiliation |
Department of Pathology, Medical University of South Carolina, Charleston, South Carolina, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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