TY - JOUR
T1 - Inhibition of p38 MAPK activity promotes ex vivo expansion of human cord blood hematopoietic stem cells
AU - Zou, Jing
AU - Zou, Ping
AU - Wang, Jie
AU - Li, Lei
AU - Wang, Yong
AU - Zhou, Daohong
AU - Liu, Lingbo
N1 - Funding Information:
Acknowledgments The authors thank Mr. Zhihui Liang and Mrs. Huifen Zhu for the flow cytometric analysis. This study was supported in part by a grant from the Chinese National Natural Science Foundation (no. 30871097) to Dr. Lingbo Liu and a grant from the National Institute of Allergy and Infectious Diseases of the United States (R01-AI080421) to Dr. Daohong Zhou.
PY - 2012/6
Y1 - 2012/6
N2 - Ex vivo expansion of hematopoietic stem cells (HSCs) depends on HSC self-renewing proliferation and functional maintenance, which can be negatively affected by HSC differentiation, apoptosis, and senescence. Therefore, inhibition of HSC senescence may promote HSC expansion. To test this hypothesis, we examined the effect of inhibition of p38 mitogen-activated protein kinase (p38) on the expansion of human umbilical cord blood (hUCB) CD133 + cells because activation of p38 has been implicated in the induction of HSC senescence under various physiological and pathological conditions. Our results showed that ex vivo expansion of hUCB CD133 + cells activated p38, which was abrogated by the p38 specific inhibitor SB203580 (SB). Inhibition of p38 activity with SB promoted the expansion of CD133 + cells and CD133 +CD38 - cells. In addition, hUCB CD133 + cells expanded in the presence of SB for 7 days showed about threefold increase in the clonogenic function of HSCs and engraftment in non-obese diabetic/severe combined immunodeficient mice after transplantation compared to the input cells. In contrast, the cells expanded without SB exhibited a significant reduction in these HSC functions. The enhancement of ex vivo expansion of hUCB HSCs is primarily attributable to SB-mediated inhibition of HSC senescence. In addition, inhibition of HSC apoptosis and upregulation of CXCR4 may also contribute to the enhancement. However, p38 inhibition had no significant effect on HSC differentiation and proliferation. These findings suggest that inhibition of p38 activation may represent a novel strategy to promote ex vivo expansion of hUCB HSCs.
AB - Ex vivo expansion of hematopoietic stem cells (HSCs) depends on HSC self-renewing proliferation and functional maintenance, which can be negatively affected by HSC differentiation, apoptosis, and senescence. Therefore, inhibition of HSC senescence may promote HSC expansion. To test this hypothesis, we examined the effect of inhibition of p38 mitogen-activated protein kinase (p38) on the expansion of human umbilical cord blood (hUCB) CD133 + cells because activation of p38 has been implicated in the induction of HSC senescence under various physiological and pathological conditions. Our results showed that ex vivo expansion of hUCB CD133 + cells activated p38, which was abrogated by the p38 specific inhibitor SB203580 (SB). Inhibition of p38 activity with SB promoted the expansion of CD133 + cells and CD133 +CD38 - cells. In addition, hUCB CD133 + cells expanded in the presence of SB for 7 days showed about threefold increase in the clonogenic function of HSCs and engraftment in non-obese diabetic/severe combined immunodeficient mice after transplantation compared to the input cells. In contrast, the cells expanded without SB exhibited a significant reduction in these HSC functions. The enhancement of ex vivo expansion of hUCB HSCs is primarily attributable to SB-mediated inhibition of HSC senescence. In addition, inhibition of HSC apoptosis and upregulation of CXCR4 may also contribute to the enhancement. However, p38 inhibition had no significant effect on HSC differentiation and proliferation. These findings suggest that inhibition of p38 activation may represent a novel strategy to promote ex vivo expansion of hUCB HSCs.
KW - Ex vivo expansion
KW - Hematopoietic stem cells
KW - Human umbilical cord blood
KW - Senescence
KW - p38
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U2 - 10.1007/s00277-011-1397-7
DO - 10.1007/s00277-011-1397-7
M3 - Article
C2 - 22258328
AN - SCOPUS:84862829412
SN - 0939-5555
VL - 91
SP - 813
EP - 823
JO - Annals of Hematology
JF - Annals of Hematology
IS - 6
ER -