Transcription Factor Levels after Forward Programming of Human Pluripotent Stem Cells with GATA1, FLI1, and TAL1 Determine Megakaryocyte versus Erythroid Cell Fate Decision.
Transcription Factor Levels after Forward Programming of Human Pluripotent Stem Cells with GATA1, FLI1, and TAL1 Determine Megakaryocyte versus Erythroid Cell Fate Decision.
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DOI：
10.1016/j.stemcr.2018.11.001
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发表时间：
2018-12-11
影响因子：
5.9
通讯作者：
Ghevaert C
中科院分区：
文献类型：
--
作者：
Dalby A;Ballester-Beltrán J;Lincetto C;Mueller A;Foad N;Evans A;Baye J;Turro E;Moreau T;Tijssen MR;Ghevaert C
人类多能干细胞 (hPSC) 在体外生产血细胞及其前体有可能对医疗保健提供产生重大影响。我们证明，通过 GATA1、FLI1 和 TAL1 的过度表达对 hPSC 进行正向编程，可产生可分化为巨核细胞或成红细胞的祖细胞群。使用“彩虹”慢病毒载体来量化单细胞中的单个转基因表达，我们证明细胞命运决定为成红细胞或巨核细胞是由 FLI1 表达水平决定的，并且与培养条件无关。早期 FLI1 表达对于赋予程序化细胞增殖潜力至关重要，而其随后的沉默或维持分别决定红细胞或巨核细胞的命运。这些定型祖细胞随后响应血小板生成素或促红细胞生成素而扩增并成熟为巨核细胞或成红细胞。我们的结果揭示了 hPSC 正向编程的分子机制以及输血医学应用的新机会。 hPSCS 中 GATA1、TAL1 和 FLI1 的过度表达产生巨核细胞和成红细胞 谱系命运是一个独立于细胞因子但由 FLI1 转基因决定的早期事件 作者表明，hPSC 中 GATA1、TAL1 和 FLI1 的过度表达导致祖细胞的形成，这些祖细胞在分化为巨核细胞或红系谱系的早期就已定型。细胞命运决定独立于所使用的细胞因子（TPO 或 EPO），但由 FLI1 转基因的水平决定。
The production of blood cells and their precursors from human pluripotent stem cells (hPSCs) in vitro has the potential to make a significant impact upon healthcare provision. We demonstrate that the forward programming of hPSCs through overexpression of GATA1, FLI1, and TAL1 leads to the production of a population of progenitors that can differentiate into megakaryocyte or erythroblasts. Using “rainbow” lentiviral vectors to quantify individual transgene expression in single cells, we demonstrate that the cell fate decision toward an erythroblast or megakaryocyte is dictated by the level of FLI1 expression and is independent of culture conditions. Early FLI1 expression is critical to confer proliferative potential to programmed cells while its subsequent silencing or maintenance dictates an erythroid or megakaryocytic fate, respectively. These committed progenitors subsequently expand and mature into megakaryocytes or erythroblasts in response to thrombopoietin or erythropoietin. Our results reveal molecular mechanisms underlying hPSC forward programming and novel opportunities for application to transfusion medicine. Overexpression of GATA1, TAL1, and FLI1 in hPSCS produces megakaryocytes and erythroblasts Lineage fate is an early event independent of cytokines but dictated by FLI1 transgene The authors show that overexpression of GATA1, TAL1, and FLI1 in hPSCs leads to the formation of progenitors that are committed early during differentiation to either the megakaryocytic or erythroid lineage. The cell fate decision is independent of the cytokines used (TPO or EPO) but is dictated by the level of the FLI1 transgene.
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影响因子：
3.7
作者：
Kurita R;Suda N;Sudo K;Miharada K;Hiroyama T;Miyoshi H;Tani K;Nakamura Y
通讯作者：
Nakamura Y
影响因子：
5.9
作者：
Hirose, Sho-ichi;Takayama, Naoya;Nakamura, Sou;Nagasawa, Kazumichi;Ochi, Kiyosumi;Hirata, Shinji;Yamazaki, Satoshi;Yamaguchi, Tomoyuki;Otsu, Makoto;Sano, Shinya;Takahashi, Nobuyasu;Sawaguchi, Akira;Ito, Mamoru;Kato, Takashi;Nakauchi, Hiromitsu;Eto, Koji
通讯作者：
Eto, Koji
影响因子：
64.8
作者：
Lis R;Karrasch CC;Poulos MG;Kunar B;Redmond D;Duran JGB;Badwe CR;Schachterle W;Ginsberg M;Xiang J;Tabrizi AR;Shido K;Rosenwaks Z;Elemento O;Speck NA;Butler JM;Scandura JM;Rafii S
通讯作者：
Rafii S
影响因子：
20.3
作者：
Griffiths, Rebecca E.;Kupzig, Sabine;Anstee, David J.
通讯作者：
Anstee, David J.
影响因子：
2.9
作者：
Ali, Akif;Auvinen, Marja-Kaisa;Rautonen, Jukka
通讯作者：
Rautonen, Jukka