Lipid Deprivation Induces a Stable, Naive-to-Primed Intermediate State of Pluripotency in Human PSCs.,Cell Stem Cell

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Lipid Deprivation Induces a Stable, Naive-to-Primed Intermediate State of Pluripotency in Human PSCs.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2019-05-30 , DOI: 10.1016/j.stem.2019.05.001
Daniela Cornacchia ₁ , Chao Zhang ₂ , Bastian Zimmer ₁ , Sun Young Chung ₁ , Yujie Fan ₃ , Mohamed A Soliman ₄ , Jason Tchieu ₁ , Stuart M Chambers ₁ , Hardik Shah ₅ , Daniel Paull ₆ , Csaba Konrad ₇ , Michelle Vincendeau ₁ , Scott A Noggle ₆ , Giovanni Manfredi ₇ , Lydia W S Finley ₈ , Justin R Cross ₅ , Doron Betel ₂ , Lorenz Studer ₁

Affiliation

Developmental Biology, The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
Developmental Biology, The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10065, USA.
Developmental Biology, The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine, New York, NY 10065, USA.
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
The New York Stem Cell Foundation Research Institute, New York, NY 10019, USA.
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA.
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

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 identifyde novolipogenesis as a common transcriptional signature of E8 hPSCs and the pre-implantation human epiblastin 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.

中文翻译：

脂质剥夺在人PSC中诱导稳定，幼稚至富集的多能性中间状态。

捕获幼稚的人类多能干细胞（hPSC）的当前挑战表明，调节人类幼稚的与致敏的多能性的因素仍未完全定义。在这里，我们证明了广泛使用的Essential 8基本培养基（E8）在从幼稚到原始的多能性中间状态下捕获hPSC，尽管提供了维持原始状态的生长因子条件，但仍表现出一些幼稚的发育，生物能和表观基因组特征。转录上，E8 hPSCs通过激活的脂质生物合成而被标记，并且抑制了MAPK /TGF-β基因的表达，从而导致内源性ERK抑制。这些特征取决于无脂质的培养条件，并且在脂质暴露后会消失，而即使在存在脂质的情况下，短期药理性ERK抑制作用也可以恢复幼稚的至引发的中间性状。最后，我们确定新生脂肪形成为E8 hPSCs和植入前人类上皮细胞在体内的常见转录特征。这些发现暗示了外源脂质在调节人类多能性中的有效性，并将E8 hPSCs定义为稳定的，从天真到致敏的中间体（NPI）多能性状态。

更新日期：2019-05-31

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