Abstract
Growing evidence supports the notion that lipid metabolism is critical for embryonic stem cell (ESC) maintenance. Recently, α/β-hydrolase domain-containing (ABHD) proteins have emerged as novel pivotal regulators in lipid synthesis or degradation while their functions in ESCs have not been investigated. In this study, we revealed the role of ABHD11 in ESC function using classical loss and gain of function experiments. Knockout of Abhd11 hampered ESC expansion and differentiation, triggering the autophagic flux and apoptosis. In contrast, Abhd11 overexpression exerted anti-apoptotic effects in ESCs. Moreover, Abhd11 knockout disturbed GSK3β/β-Catenin and ERK signaling transduction. Finally, Abhd11 knockout led to the misexpression of key metabolic enzymes related to lipid synthesis, glycolysis, and amino acid metabolism, and ABHD11 contributed to the homeostasis of lipid metabolism. These findings provide new insights into the broad role of ABHD proteins and highlight the significance of regulators of lipid metabolism in the control of stem cell function.
Highlights
Embryonic stem cells (ESCs) are derived from the inner cell mass of early preimplantation embryo and can proliferate unlimitedly while maintaining the potential to differentiate into all somatic lineages (Nichols and Smith, 2011)
To investigate whether alpha/beta hydrolase domain (ABHD) proteins were implicated in mouse embryonic stem cell (ESC) maintenance, we first analyzed ESC transcriptome data (Supplementary Table S1) and a published genome-scale CRISPR-Cas9 knockout ESC dataset, in which genes essential for ESC self-renewal are ranked (Tzelepis et al, 2016)
We found that Abhd11 and Abhd10 were downregulated, while most other ABHD family genes, such as Abhd 1, 3, 5, 6, and 7 were upregulated in OCT4-negative cells (Supplementary Figure S1C)
Summary
Embryonic stem cells (ESCs) are derived from the inner cell mass of early preimplantation embryo and can proliferate unlimitedly while maintaining the potential to differentiate into all somatic lineages (Nichols and Smith, 2011). Due to their self-renewal ability and pluripotency, ESCs represent a cell model for recapitulating and investigating the developmental processes, and offer unique opportunities in regenerative medicine (Wu and Belmonte, 2016). A molecular understanding of cellular metabolic homeostasis during self-renewal is essential for harnessing the full potential of ESCs. It has been established that glucose and amino acid metabolism, along with transcriptional and epigenetic regulation, are critical for ESC pluripotency and reprogramming. Glycolysis, which mediates changes in acetyl-CoA and histone acetylation, controls ESC proliferation, pluripotency, and differentiation
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