Erythropoiesis from human embryonic stem cells through erythropoietin-independent AKT signaling.
Erythropoiesis from human embryonic stem cells through erythropoietin-independent AKT signaling.
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DOI：
10.1002/stem.1677
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发表时间：
2014-06
期刊：
影响因子：
5.2
通讯作者：
Crooks, Gay M.
中科院分区：
文献类型：
--
作者：
Kim, William S.;Zhu, Yuhua;Deng, Qiming;Chin, Chee Jia;He, Chong Bin;Grieco, Amanda J.;Dravid, Gautam G.;Parekh, Chintan;Hollis, Roger P.;Lane, Timothy F.;Bouhassira, Eric E.;Kohn, Donald B.;Crooks, Gay M.
无限的自我更新能力和分化潜力使人多能干细胞（PSC）成为安全输血用红细胞（RBC）离体生产的有希望的来源。目前从PSC诱导红细胞生成的方法存在RBC产量低的问题，其中大多数是不成熟的并且含有胚胎和胎儿而不是成人血红蛋白。我们以前已经表明，同源二聚化的细胞内成分的MPL（ic-MPL）诱导人脐带血祖细胞的红细胞生成。本研究的目的是探讨ic-MPL二聚体诱导人胚胎干细胞（hESC）红细胞生成的潜力，并确定这种策略激活的信号通路。我们在这里提出的证据表明，ic-MPL二聚化诱导促红细胞生成素（EPO）的非依赖性红细胞分化从hESC诱导红细胞祖细胞的产生，并通过促进更有效的红细胞成熟，增加红细胞去核以及增加γ：β-珠蛋白的比例和生产β-珠蛋白。ic-MPL二聚化在诱导红细胞生成方面比EPO显著更有效，并且其作用是EPO的相加作用。信号转导研究表明，与野生型MPL受体的刺激不同，ic-MPL的二聚化在JAK 2/STAT 5信号转导不存在的情况下激活AKT。AKT激活上调加塔-1和FOXO 3转录途径，导致抑制细胞凋亡、调节细胞周期和增强红系细胞成熟。这些发现为从hPSC产生治疗相关的RBC产物开辟了潜在的新靶点。
Unlimited self renewal capacity and differentiation potential make human pluripotent stem cells (PSC) a promising source for the ex vivo manufacture of red blood cells (RBC) for safe transfusion. Current methods to induce erythropoiesis from PSC suffer from low yields of RBCs, most of which are immature and contain embryonic and fetal rather than adult hemoglobins. We have previously shown that homo-dimerization of the intracellular component of MPL (ic-MPL) induces erythropoiesis from human cord blood progenitors. The goal of the present study was to investigate the potential of ic-MPL dimerization to induce erythropoiesis from human embryonic stem cells (hESC) and to identify the signaling pathways activated by this strategy. We present here evidence that ic-MPL dimerization induces erythropoietin (EPO)-independent erythroid differentiation from hESC by inducing the generation of erythroid progenitors and by promoting more efficient erythroid maturation with increased RBC enucleation as well as increased gamma:epsilon globin ratio and production of beta-globin protein. ic-MPL dimerization is significantly more potent than EPO in inducing erythropoiesis and its effect is additive to EPO. Signaling studies show that dimerization of ic-MPL, unlike stimulation of the wild type MPL receptor, activates AKT in the absence of JAK2/STAT5 signaling. AKT activation upregulates the GATA-1 and FOXO3 transcriptional pathways with resulting inhibition of apoptosis, modulation of cell cycle and enhanced maturation of erythroid cells. These findings open up potential new targets for the generation of therapeutically relevant RBC products from hPSC.
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影响因子：
9.8
作者：
Kadri Z;Shimizu R;Ohneda O;Maouche-Chretien L;Gisselbrecht S;Yamamoto M;Romeo PH;Leboulch P;Chretien S
通讯作者：
Chretien S
影响因子：
20.3
作者：
Gregory, T;Yu, CN;Weiss, MJ
通讯作者：
Weiss, MJ
影响因子：
10.4
作者：
Kaushansky, K.
通讯作者：
Kaushansky, K.
影响因子：
39.2
作者：
Carson, Jeffrey L.;Grossman, Brenda J.;Djulbegovic, Benjamin
通讯作者：
Djulbegovic, Benjamin
影响因子：
4.8
作者：
Drachman, JG;Millett, KM;Kaushansky, K
通讯作者：
Kaushansky, K