Inhibition of p38 mitogen-activated protein kinase promotes ex vivo hematopoietic stem cell expansion

Yong Wang, Joshua Kellner, Lingbo Liu, Daohong Zhou

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

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 μM) 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.

Original languageEnglish (US)
Pages (from-to)1143-1152
Number of pages10
JournalStem Cells and Development
Volume20
Issue number7
DOIs
StatePublished - Jul 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Developmental Biology
  • Cell Biology

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