Tnfaip2/exoc3-driven lipid metabolism is essential for stem cell differentiation and organ homeostasis.
Tnfaip2/exoc3-driven lipid metabolism is essential for stem cell differentiation and organ homeostasis.
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DOI：
10.15252/embr.201949328
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发表时间：
2021-01-07
期刊：
影响因子：
7.7
通讯作者：
Rudolph KL
中科院分区：
文献类型：
--
作者：
Deb S;Felix DA;Koch P;Deb MK;Szafranski K;Buder K;Sannai M;Groth M;Kirkpatrick J;Pietsch S;Gollowitzer A;Groß A;Riemenschneider P;Koeberle A;González-Estévez C;Rudolph KL
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 的敲除会破坏由体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）可恢复 Smed-exoc3 耗尽的涡虫中 Tnfaip2 缺陷的 ESC 的分化能力和器官维持能力。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。这项研究表明，脂质代谢是小鼠 ESC 分化和涡虫器官维持所必需的。
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. This study shows that lipid metabolism is required for mouse ESC differentiation and organ maintenance in planarians.