Lipid Deprivation Induces a Stable, Naive-to-Primed Intermediate State of Pluripotency in Human PSCs.
Lipid Deprivation Induces a Stable, Naive-to-Primed Intermediate State of Pluripotency in Human PSCs.
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DOI：
10.1016/j.stem.2019.05.001
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发表时间：
2019-07-03
期刊：
影响因子：
23.9
通讯作者：
Studer L
中科院分区：
文献类型：
--
作者：
Cornacchia D;Zhang C;Zimmer B;Chung SY;Fan Y;Soliman MA;Tchieu J;Chambers SM;Shah H;Paull D;Konrad C;Vincendeau M;Noggle SA;Manfredi G;Finley LWS;Cross JR;Betel D;Studer L
目前在捕获幼稚人多能干细胞（hPSC）方面的挑战表明，调节人幼稚与引发多能性的因素仍然不完全确定。在这里，我们证明了广泛使用的必需8基本培养基（E8）捕获hPSC在幼稚到引发的多能性中间状态，表达几个幼稚样发育，生物能量和表观基因组特征，尽管提供引发状态维持生长因子条件。在转录上，E8 hPSC以激活的脂质生物合成和抑制的MAPK/TGF-β基因表达为标志，导致内源性ERK抑制。这些特征依赖于无脂质培养条件，并且在脂质暴露后丢失，而短期药理学ERK抑制即使在脂质存在下也能恢复幼稚至引发的中间性状。最后，我们确定从头脂肪生成是E8 hPSC和体内植入前人上胚层的共同转录特征。这些发现暗示外源脂质可用于调节人多能性，并将E8 hPSC定义为稳定的、幼稚至致敏中间体（NPI）多能状态。人类幼稚多能性的调节仍然不完全清楚。Cornacchia等人表明，无脂质培养条件足以通过内源性ERK抑制使人多能干细胞偏向幼稚至致敏中间状态。转录组学分析表明，通过从头脂肪生成的多能性调节模拟植入前发育期间的体内调节。
Current challenges in capturing naive human pluripotent stem cells (hPSCs) suggest that the factors regulating human naive versus primed pluripotency remain incompletely defined. Here we demonstrate that the widely used Essential 8 minimal medium (E8) captures hPSCs at a naive-to-primed intermediate state of pluripotency expressing several naive-like developmental, bioenergetic, and epigenomic features despite providing primed-state-sustaining growth factor conditions. Transcriptionally, E8 hPSCs are marked by activated lipid biosynthesis and suppressed MAPK/TGF-β gene expression, resulting in endogenous ERK inhibition. These features are dependent on lipid-free culture conditions and are lost upon lipid exposure, whereas short-term pharmacological ERK inhibition restores naive-to-primed intermediate traits even in the presence of lipids. Finally, we identify de novo lipogenesis as a common transcriptional signature of E8 hPSCs and the pre-implantation human epiblast in vivo. These findings implicate exogenous lipid availability in regulating human pluripotency and define E8 hPSCs as a stable, naive-to-primed intermediate (NPI) pluripotent state. The regulation of human naive pluripotency remains incompletely understood. Cornacchia et al. show that lipid-free culture conditions are sufficient to skew human pluripotent stem cells toward a naive-to-primed intermediate state via endogenous ERK inhibition. Transcriptomic analyses suggest that pluripotency regulation via de novo lipogenesis mimics in vivo regulation during pre-implantation development.
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.1004584107
发表时间：
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作者：
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影响因子：
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作者：
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