PT  - JOURNAL ARTICLE
AU  - Chanchal Thomas Mannully
AU  - Reut Bruck-Haimson
AU  - Anish Zacharia
AU  - Paul Orih
AU  - Alaa Shehadeh
AU  - Daniel Saidemberg
AU  - Natalya M Kogan
AU  - Sivan Alfandary
AU  - Raphael Serruya
AU  - Arie Dagan
AU  - Isabelle Petit
AU  - Arieh Moussaieff
TI  - Lipid Desaturation Regulates the Balance between Self-renewal and Differentiation in Mouse Blastocyst-derived Stem Cells
AID  - 10.1101/2022.07.28.501839
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.07.28.501839
4099  - http://biorxiv.org/content/early/2022/11/22/2022.07.28.501839.short
4100  - http://biorxiv.org/content/early/2022/11/22/2022.07.28.501839.full
AB  - Stem cells are defined by their ability to self-renew and to 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 upregulated stearoyl-CoA desaturase-1 (Scd1) in ESCs, 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. 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 point to lipid desaturation as 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. In contrast, mono unsaturated fatty acids (MUFAs), known to be essential for ESCs are detrimental to TSCs.Competing Interest StatementThe authors have declared no competing interest.