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

Abstract

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-exoc3depleted 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.

Proteomic analysis of bone marrow-derived mesenchymal stem cell extracellular vesicles from healthy donors: implications for proliferation, angiogenesis, Wnt signaling, and the basement membrane

“…We hypothesized that BM-MSC EVs would contain angiogenesis-related cargo. Donor 1 and donor 2 shared three angiogenesis-related proteins in common: Neuropilin-1 (NRP1) [ 44 – 50 ], tumor necrosis factor alpha-induced protein 2 (TNFAIP2) [ 51 ], and Sushi repeat-containing protein (SRPX2) [ 52 ] (Fig. 5 A), which have all been demonstrated to be modulators of angiogenesis.…”

Intestine-enrichedapolipoprotein borthologs are required for stem cell differentiation and regeneration in planarians

“…Intriguingly, FA oxidation is a significant source of carbon for acetyl-CoA production and histone acetylation 69 . Consistent with a role for NLs in planarian differentiation, knockdown of exoc3 reduces triglyceride levels, causes expansion of the neoblast population, inhibits organogenesis, and reduces expression of differentiation markers; palmitic acid supplementation rescues these differentiation-associated phenotypes 66 .…”

“…Intriguingly, FA oxidation is a significant source of carbon for acetyl-CoA production and histone acetylation 69 . Consistent with a role for NLs in planarian differentiation, knockdown of exoc3 reduces triglyceride levels, causes expansion of the neoblast population, inhibits organogenesis, and reduces expression of differentiation markers; palmitic acid supplementation rescues these differentiation-associated phenotypes 66 . Furthermore, in the sexually reproducing S. mediterranea planarian biotype, inhibition of nuclear hormone receptor 1 causes NL accumulation and blocks differentiation of gonads and accessory reproductive tissues, a phenotype that is rescued by supplementation with either acetyl-CoA or Acyl-CoA synthetase 70 .…”

“…Intriguingly, inhibition of other planarian genes required for differentiation (e.g., the transcription factor mex3-1, the extracellular matrix component collagen4-1, and the transcriptional co-activating protein cbp-3) also cause increases in neoblast numbers in vivo 52,[63][64][65] . Furthermore, knockdown of exocyst component 3 (exoc3), a negative regulator of pluripotency whose mammalian homolog Tnfaip3 promotes embryonic stem cell differentiation, causes expansion of the S/G2/M (X1) neoblast fraction 66 . We speculate that these genes may be required for cell fate specification, and that their inhibition shifts neoblast dynamics in favor of renewal divisions that expand the stem cell compartment.…”

Regeneration in starved planarians depends on TRiC/CCT subunits modulating the unfolded protein response

“…We reasoned that if cct3A(RNAi) planarians were deficient in energy, supplementation with a dietary source of fuel such as fatty acids could rescue cct3A(RNAi) phenotypes. We injected palmitic acid (PA), one of the most abundant fatty acids in animals, and its mobilized form palmitoyl‐ L ‐carnitine (PC) before RNAi injection in starved conditions as done previously (Deb et al , 2021 ). Interestingly, PA/PC significantly increased the survival of cct3A(RNAi) planarians (Fig 7B and C ).…”