Tnfaip2/exoc3 ‐driven lipid metabolism is essential for stem cell differentiation and organ homeostasis

Abstract

Lipid metabolism influences stem cell maintenance and differenti- ation but genetic factors that control these processes remain to be delineated. Here, we identify Tnfaip2 as an inhibitor of reprogram- ming 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 differen- tiate, Tnfaip2-deficient ESCs fail to induce synthesis of cellular tria- cylglycerol (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 essen- tial for ESC differentiation and planarian organ maintenance.