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Tnfaip2/Exoc3 driven lipid metabolism is essential for stem cell differentiation & organ homeostasis [Mus musculus, 1]

ABSTRACT: Lipid metabolism is recognized as a key process for stem cell maintenance and differentiation but genetic factors that instruct stem cell function by influencing lipid metabolism remain to be delineated. Here we identify Tnfaip2 as an inhibitor of reprogramming of mouse fibroblasts into induced pluripotent stem cells. Tnfaip2 knockout embryonic stem cells (ESCs) exhibit differentiation failure and knockdown of the planarian orthologue, Smed-exoc3, abrogates in vivo differentiation of somatic stem cells, tissue homeostasis, and regeneration. Tnfaip2 deficient ESCs fail to induce synthesis of cellular triacylglycerol (TAG) and lipid droplets (LD) coinciding with reduced expression of Vimentin (Vim) – a known inducer of LD formation. Knockdown of Vim and Tnfaip2 act epistatically in enhancing cellular reprogramming of mouse fibroblasts. Similarly, planarians devoid of Smed-exoc3 displayed acute loss of TAGs. Supplementation of palmitic acid (PA) and palmitoyl-L-carnitine (a mitochondrial carrier of PA) restores the differentiation capacity of Tnfaip2 deficient ESCs as well as stem cell differentiation and organ maintenance in Smed-exoc3-depleted planarians. Together, these results identify a novel pathway, which is essential for stem cell differentiation and organ maintenance by instructing lipid metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE134301 | GEO | 2020/11/16

REPOSITORIES: GEO

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Tnfaip2/Exoc3 driven lipid metabolism is essential for stem cell differentiation & organ homeostasis [Schmidtea mediterranea]

Project description:Lipid metabolism is recognized as a key process for stem cell maintenance and differentiation but genetic factors that instruct stem cell function by influencing lipid metabolism remain to be delineated. Here we identify Tnfaip2 as an inhibitor of reprogramming of mouse fibroblasts into induced pluripotent stem cells. Tnfaip2 knockout embryonic stem cells (ESCs) exhibit differentiation failure and knockdown of the planarian orthologue, Smed-exoc3, abrogates in vivo differentiation of somatic stem cells, tissue homeostasis, and regeneration. Tnfaip2 deficient ESCs fail to induce synthesis of cellular triacylglycerol (TAG) and lipid droplets (LD) coinciding with reduced expression of Vimentin (Vim) – a known inducer of LD formation. Knockdown of Vim and Tnfaip2 act epistatically in enhancing cellular reprogramming of mouse fibroblasts. Similarly, planarians devoid of Smed-exoc3 displayed acute loss of TAGs. Supplementation of palmitic acid (PA) and palmitoyl-L-carnitine (a mitochondrial carrier of PA) restores the differentiation capacity of Tnfaip2 deficient ESCs as well as stem cell differentiation and organ maintenance in Smed-exoc3-depleted planarians. Together, these results identify a novel pathway, which is essential for stem cell differentiation and organ maintenance by instructing lipid metabolism.

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Tnfaip2/Exoc3 controls exit from pluripotency by mediating lipid droplet formation and FA-induced differentiation

Project description:The decline in stem cell function leads to impairments in tissue homeostasis but genetic factors that control differentiation and de-differentiation of stem cells in the context of tissue homeostasis remain to be delineated. Here we show that Tnfaip2 (a target gene of TNFa/NFkB signaling) has an essential role for the differentiation of pluripotent, embryonic stem cells (ESCs). Knockdown of the planarian pseudo-orthologue, Smed-exoc3, impairs pluripotent stem cell differentiation, tissue homeostasis and regeneration in vivo. The study shows that Tnfaip2 deletion impairs changes in lipid metabolism that drive differentiation induction of ESCs. The application of palmitic acid (PA, the most abundant saturated fatty acid in mammalian cells) and palmitoylcarnitine (a mitochondrial carrier of PA) fully restores the differentiation of ESCs as well as the differentiation of pluripotent stem cells and organ maintenance in Smed-exoc3-depleted planarians. Together, these results identify a novel pathway downstream of TNFa/NFkB signaling, which is essential for exit from pluripotency by mediating changes in lipid metabolism.

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A mex3 homolog is required for differentiation during planarian stem cell lineage development

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