TY - JOUR
T1 - Inhibition of p38 mitogen-activated protein kinase promotes ex vivo hematopoietic stem cell expansion
AU - Wang, Yong
AU - Kellner, Joshua
AU - Liu, Lingbo
AU - Zhou, Daohong
PY - 2011/7/1
Y1 - 2011/7/1
N2 - 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.
AB - 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.
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U2 - 10.1089/scd.2010.0413
DO - 10.1089/scd.2010.0413
M3 - Article
C2 - 21198398
AN - SCOPUS:79959818068
SN - 1547-3287
VL - 20
SP - 1143
EP - 1152
JO - Stem Cells and Development
JF - Stem Cells and Development
IS - 7
ER -