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

Abstract

Little is known about how lipid mobilization and utilization are modulated during stem-cell-driven tissue growth during regeneration. Planarian flatworms can regenerate all missing tissues in 10 days due to the proliferation and differentiation of pluripotent somatic stem cells called neoblasts. In planarians, diet-derived neutral lipids are stored in the intestine. Here, we identify two intestine-enriched paralogs of apolipoprotein b, apob-1 and apob-2, that are required for regeneration. Consistent with apolipoproteins' known roles regulating neutral lipid (NL) transport in lipoprotein particles (LPs), NLs increased in the intestine upon simultaneous dsRNA-mediated knockdown of apob-1 and apob-2, but were depleted in neoblasts and their progeny. apob knockdown reduced regeneration blastema morphogenesis, and delayed re-establishment of axial polarity and regeneration of multiple organs. Using flow cytometry, we found that neoblast progeny accumulated in apob(RNAi) animals, with minimal effects on neoblast maintenance or proliferation. In addition, ApoB reduction primarily dysregulated expression of transcripts enriched in neoblast progeny and mature cell types, compared to cycling neoblasts. Together, our results provide evidence that intestine-derived lipids serve as a source of metabolites required for neoblast differentiation. In addition, these findings demonstrate that planarians are a tractable model for elucidating specialized mechanisms by which lipid metabolism must be regulated during animal regeneration.

Decoding Stem Cells: An Overview on Planarian Stem Cell Heterogeneity and Lineage Progression

“…Examples of such factors include the already mentioned MEX3 RNA-binding protein, since the silencing of its expression results in the expansion of the stem cell compartment in parallel with a decrease in the number of lineage-restricted progenitors committed towards eye, brain, pharynx and protonephridia fates [8]. In contrast, the silencing of apolipoprotein b triggers stem cell progeny accumulation without affecting neoblast maintenance or proliferation, suggesting that intestine-derived lipids may serve as a source of metabolites needed for neoblast differentiation [107]. The accumulation of key stem cell markers have been shown to occur in neoblasts that fail to differentiate following the silencing of not1, a central scaffolding protein of the CCR4-NOT complex involved in mRNA degradation through deadenylation [108].…”