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

• Published in: Cell stem cell Vol. 25; no. 1; pp. 120 - 136.e10
• Main Authors: Cornacchia, Daniela, Zhang, Chao, Zimmer, Bastian, Chung, Sun Young, Fan, Yujie, Soliman, Mohamed A., Tchieu, Jason, Chambers, Stuart M., Shah, Hardik, Paull, Daniel, Konrad, Csaba, Vincendeau, Michelle, Noggle, Scott A., Manfredi, Giovanni, Finley, Lydia W.S., Cross, Justin R., Betel, Doron, Studer, Lorenz
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.07.2019
• Subjects: differential human pluripotent states; endogenous ERK inhibition; lipid metabolism; metabolic regulation of cell identity; metabolism and epigenetics; metabolism and pluripotency; naive-to-primed intermediate pluripotency; pluripotency regulation through lipids; pluripotency regulation through lipids; naive-to-primed intermediate pluripotency; endogenous ERK inhibition; metabolic regulation of cell identity; lipid metabolism; metabolism and pluripotency; metabolism and epigenetics; differential human pluripotent states
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2019.05.001

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. [Display omitted] •Essential 8 (E8) hPSCs exhibit naive-to-primed intermediate (NPI) pluripotency features•NPI traits are dependent on lipid-free E8 composition•Lipid deprivation triggers endogenous ERK inhibition despite exposure to high FGF2•De novo lipogenesis marks transcriptomes of E8 hPSCs and human pre-implantation epiblast 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.