Inhibition of p38 MAPK activity promotes ex vivo expansion of human cord blood hematopoietic stem cells.
Inhibition of p38 MAPK activity promotes ex vivo expansion of human cord blood hematopoietic stem cells.
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DOI：
10.1007/s00277-011-1397-7
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发表时间：
2012-06
影响因子：
3.5
通讯作者：
Liu, Lingbo
中科院分区：
文献类型：
--
作者：
Zou, Jing;Zou, Ping;Wang, Jie;Li, Lei;Wang, Yong;Zhou, Daohong;Liu, Lingbo
造血干细胞（HSC）的体外扩增依赖于HSC的自我更新增殖和功能维持，这可能受到HSC分化、凋亡和衰老的负面影响。因此，抑制HSC衰老可促进HSC扩增。为了验证这一假设，我们研究了抑制p38丝裂原活化蛋白激酶（p38）对人脐带血（hUCB）CD 133+细胞扩增的影响，因为p38的活化与各种生理和病理条件下HSC衰老的诱导有关。我们的结果表明，hUCB CD 133+细胞的体外扩增激活了p38，这被p38特异性抑制剂SB 203580（SB）废除。用SB抑制p38活性促进了CD 133+细胞和CD 133 + CD 38 −细胞的扩增。此外，与输入细胞相比，在SB存在下扩增7天的hUCB CD 133+细胞在移植后在非肥胖糖尿病/严重联合免疫缺陷小鼠中显示出HSC的克隆形成功能和植入的约三倍增加。相反，没有SB扩增的细胞表现出这些HSC功能的显著降低。hUCB HSC离体扩增的增强主要归因于SB介导的对HSC衰老的抑制。此外，抑制HSC凋亡和上调CXCR 4也可能有助于增强。而p38抑制对HSC的分化和增殖无明显影响。这些发现表明，抑制p38活化可能代表了促进hUCB HSC体外扩增的新策略。
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.
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DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
4.8
作者：
Kelly SS;Sola CB;de Lima M;Shpall E
通讯作者：
Shpall E
影响因子：
2.6
作者：
Araki H;Baluchamy S;Yoshinaga K;Petro B;Petiwala S;Parajuli R;Milhem M;Lavelle D;DeSimone J;Mahmud N
通讯作者：
Mahmud N
影响因子：
20.3
作者：
Nagata, Y;Moriguchi, T;Todokoro, K
通讯作者：
Todokoro, K
影响因子：
4.3
作者：
de Latour, Regis Peffault;Purtill, Duncan;Rocha, Vanderson
通讯作者：
Rocha, Vanderson