Lipid metabolism influences stem cell maintenance and differentiation but genetic factors that control these processes remain to be delineated. Here, we identify Tnfaip2 as an inhibitor of reprogramming of mouse fibroblasts into induced pluripotent stem cells. Tnfaip2 knockout impairs differentiation of embryonic stem cells (ESCs), and knockdown of the planarian para‐ortholog, Smed‐exoc3, abrogates in vivo tissue homeostasis and regeneration—processes that are driven by somatic stem cells. When stimulated to differentiate, 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. Smed‐exoc3 depletion also causes a strong reduction of TAGs in planarians. The study shows that Tnfaip2 acts epistatically with and upstream of Vim in impairing cellular reprogramming. Supplementing palmitic acid (PA) and palmitoyl‐L‐carnitine (the mobilized form of PA) restores the differentiation capacity of Tnfaip2‐deficient ESCs and organ maintenance in Smed‐exoc3‐depleted planarians. Together, these results identify a novel role of Tnfaip2 and exoc3 in controlling lipid metabolism, which is essential for ESC differentiation and planarian organ maintenance.

中文翻译：

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Tnfaip2/exoc3驱动的脂质代谢对于干细胞分化和器官稳态至关重要


脂质代谢影响干细胞的维持和分化，但控制这些过程的遗传因素仍有待阐明。在这里，我们确定Tnfaip2是小鼠成纤维细胞重编程为诱导多能干细胞的抑制剂。 Tnfaip2敲除会损害胚胎干细胞 (ESC) 的分化，而涡虫副直系同源物Smed-exoc3的敲除则会破坏由体细胞干细胞驱动的体内组织稳态和再生过程。当刺激分化时， Tnfaip2缺陷的 ESC 无法诱导细胞三酰甘油 (TAG) 和脂滴 (LD) 的合成，这与波形蛋白 ( Vim )（一种已知的 LD 形成诱导剂）表达减少相一致。 Smed-exoc3耗竭也会导致涡虫中 TAG 的大幅减少。研究表明， Tnfaip2与Vim一起上位并在 Vim 上游发挥作用，损害细胞重编程。补充棕榈酸 (PA) 和棕榈酰左旋肉碱（PA 的动员形式）可以恢复Tnfaip2缺陷的 ESC 的分化能力和Smed-exoc3耗尽的涡虫的器官维持能力。总之，这些结果确定了Tnfaip2和exoc3在控制脂质代谢中的新作用，这对于 ESC 分化和涡虫器官维持至关重要。