Lipid desaturation regulates the balance between self-renewal and differentiation in mouse blastocyst-derived stem cells

Abstract

Stem cells are defined by their ability to self-renew and differentiate, both shown in multiple studies to be regulated by metabolic processes. To decipher metabolic signatures of self-renewal in blastocyst-derived stem cells, we compared early differentiating embryonic stem cells (ESCs) and their extra-embryonic counterparts, trophoblast (T)SCs to their self-renewing counterparts. A metabolomics analysis pointed to the desaturation of fatty acyl chains as a metabolic signature of differentiating blastocyst-derived SCs via the upregulation of delta-6 desaturase (D6D; FADS2) and delta-5 desaturase (D5D; FADS1), key enzymes in the biosynthesis of polyunsaturated fatty acids (PUFAs). The inhibition of D6D or D5D by specific inhibitors or SiRNA retained stemness in ESCs and TSCs, and attenuated endoplasmic reticulum (ER) stress-related apoptosis. D6D inhibition in ESCs upregulated stearoyl-CoA desaturase-1 (Scd1), essential to maintain ER homeostasis. In TSCs, however, D6D inhibition downregulated Scd1. TSCs show higher Scd1 mRNA expression and high levels of monounsaturated fatty acyl chain products in comparison to ESCs. The addition of oleic acid, the product of Scd1 (essential for ESCs), to culture medium, was detrimental to TSCs. Interestingly, TSCs express a high molecular mass variant of Scd1 protein, hardly expressed by ESCs. Taken together, our data suggest that lipid desaturation is a metabolic regulator of the balance between differentiation and self-renewal of ESCs and TSCs. They point to lipid polydesaturation as a driver of differentiation in both cell types. Monounsaturated fatty acids (MUFAs), essential for ESCs are detrimental to TSCs.

Oleanolic Acid Inhibits SCD1 Gene Expression to Ameliorate Fructose‐Induced Hepatosteatosis through SREBP1c‐Dependent and ‐Independent Mechanisms

“…Moreover, SCD1 regulations have a central role in lipid homeostasis. [ 46 ] We further investigated how OA affected hepatic lipid accumulation within HFD‐fed SCD1 −/− mice that also received high levels of exogenous OLA.…”

Crosstalk between Signaling Pathways and Energy Metabolism in Pluripotency

“…On the other hand, de novo fatty acid synthesis for pluripotency has been demonstrated through multiple examples. The activity of fatty acid synthase (FASN) (67) and stearoyl-CoA desaturate (SCD1), a key enzyme in monounsaturated fatty acid (MUFA) biosynthesis (73,74), is crucial for human ESC (hESC) survival as chemically inhibiting either of these enzymes prompts massive cell death (Fig. 2B).…”