Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1-expanded human cord blood CD34(+) cells via inhibition of senescence.
Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1-expanded human cord blood CD34(+) cells via inhibition of senescence.
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DOI：
10.1002/sctm.20-0129
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发表时间：
2020-12
影响因子：
6
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Li X;Ma X;Chen Y;Peng D;Wang H;Chen S;Xiao Y;Li L;Zhou H;Cheng F;Gao Y;Chang J;Cheng T;Liu L
离体扩增的造血干细胞（HSC）的干细胞性通常受到当前方法的损害。为探讨分化抑制剂Stem Regenin 1（SR 1）对人脐带血（hUCB）CD 34+细胞体外扩增的HSC干性维持失败的机制，我们检测了p38丝裂原活化蛋白激酶α（p38 mitogen activated protein kinase α，p38 MAPK α）的活性。（p38 MAPKα，p38α）和哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1），以及它们对SR 1扩增的hUCB CD 34+细胞的影响。我们的结果表明，细胞衰老发生在SR 1扩增的hUCB CD 34+细胞中，其中p38α和mTORC 1相继被激活。此外，它们的共抑制导致hUCB CD 34+细胞衰老的进一步降低而不影响细胞凋亡，促进扩增的表型HSC的维持而不抑制分化，增加多个谱系的造血重建能力，并增强来自NOD/Shi-scid/IL-2 R γnull小鼠中SR 1扩增的hUCB CD 34+细胞的HSC的长期自我更新能力。我们的机制研究表明，衰老抑制我们的策略主要是由于下调剪接体，蛋白酶体形成，嘧啶代谢信号通路。这些结果表明，活化的p38α和mTORC 1的共抑制通过衰老抑制增强了来自SR 1扩增的hUCB CD 34+细胞的HSC的干性维持。因此，我们建立了一种新的策略，通过共抑制多个独立的衰老起始信号通路来维持离体分化抑制剂扩增的人HSC的干细胞性。这种衰老抑制诱导的离体扩增的HSC的干性维持在其他HSC扩增系统中也可能具有重要作用。在干细胞再生素1（SR 1）扩增的人脐带血（hUCB）CD 34+细胞中，p38α和雷帕霉素复合物1的哺乳动物靶标均被激活。它们的共抑制主要通过剪接体、蛋白酶体形成和嘧啶代谢信号通路的下调，通过衰老抑制维持来自SR 1扩增的hUCB CD 34+细胞的造血干细胞（HSC）的干细胞性。这种衰老抑制诱导的离体扩增的HSC的干性维持也可以在其他HSC扩增系统中发挥重要作用。
The stemness of ex vivo expanded hematopoietic stem cells (HSCs) is usually compromised by current methods. To explore the failure mechanism of stemness maintenance of human HSCs, which were expanded from human umbilical cord blood (hUCB) CD34+ cells, by differentiation inhibitor Stem Regenin 1 (SR1), an antagonist of aryl hydrocarbon receptor, we investigated the activity of p38 mitogen‐activated protein kinase α (p38 MAPKα, p38α) and mammalian target of rapamycin complex 1 (mTORC1), and their effect on SR1‐expanded hUCB CD34+ cells. Our results showed that cellular senescence occurred in the SR1‐expanded hUCB CD34+ cells in which p38α and mTORC1 were successively activated. Furthermore, their coinhibition resulted in a further decrease in hUCB CD34+ cell senescence without an effect on apoptosis, promoted the maintenance of expanded phenotypic HSCs without differentiation inhibition, increased the hematopoietic reconstitution ability of multiple lineages, and potentiated the long‐term self‐renewal capability of HSCs from SR1‐expanded hUCB CD34+ cells in NOD/Shi‐scid/IL‐2Rγnull mice. Our mechanistic study revealed that senescence inhibition by our strategy was mainly attributed to downregulation of the splicesome, proteasome formation, and pyrimidine metabolism signaling pathways. These results suggest that coinhibition of activated p38α and mTORC1 potentiates stemness maintenance of HSCs from SR1‐expanded hUCB CD34+ cells via senescence inhibition. Thus, we established a new strategy to maintain the stemness of ex vivo differentiation inhibitor‐expanded human HSCs via coinhibition of multiple independent senescence initiating signal pathways. This senescence inhibition‐induced stemness maintenance of ex vivo expanded HSCs could also have an important role in other HSC expansion systems. Both p38α and mammalian target of rapamycin complex 1 are activated in Stem Regenin 1 (SR1)‐expanded human umbilical cord blood (hUCB) CD34+ cells. Their coinhibition maintains the stemness of hematopoietic stem cells (HSCs) from SR1‐expanded hUCB CD34+ cells through senescence inhibition mainly via downregulation of the splicesome, proteasome formation, and pyrimidine metabolism signaling pathways. This senescence inhibition‐induced stemness maintenance of ex vivo expanded HSCs could also play an important role in other HSC expansion systems.
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影响因子：
82.9
作者：
Guo B;Huang X;Lee MR;Lee SA;Broxmeyer HE
通讯作者：
Broxmeyer HE
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
DOI：
10.1007/978-1-4939-1133-2_14
发表时间：
2014-01-01
期刊：
HEMATOPOIETIC STEM CELL PROTOCOLS, 3RD EDITION
影响因子：
--
作者：
Doan, Phuong L.;Chute, John P.
通讯作者：
Chute, John P.
影响因子：
3.4
作者：
Li, Xiaoyi;Ye, Fang;Chen, Jun
通讯作者：
Chen, Jun
DOI：
10.1126/science.1256337
发表时间：
2014-09-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fares I;Chagraoui J;Gareau Y;Gingras S;Ruel R;Mayotte N;Csaszar E;Knapp DJ;Miller P;Ngom M;Imren S;Roy DC;Watts KL;Kiem HP;Herrington R;Iscove NN;Humphries RK;Eaves CJ;Cohen S;Marinier A;Zandstra PW;Sauvageau G
通讯作者：
Sauvageau G