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LGR6 marks nephron progenitor cells

ABSTRACT: Background: Nephron progenitor cells (NPCs) undergo a stepwise process to generate all mature nephron structures. Mesenchymal to epithelial transition (MET) is considered a multi-step process of NPC differentiation to ensure progressive establishment of new nephrons. However, despite this important role, to date, no marker for NPCs undergoing MET in the nephron exists. Results: Here, we identify LGR6 as a NPC marker, expressed in very early cap mesenchyme, pre-tubular aggregates, renal vesicles and in segments of S-shaped bodies, following the trajectory of MET. By using a lineage tracing approach in embryonic explants in combination with confocal imaging and single-cell RNA sequencing, we provide evidence for the multiple fates of LGR6+ cells during embryonic nephrogenesis. Moreover, by using long-term in vivo lineage tracing, we show that postnatal LGR6+ cells are capable of generating the multiple lineages of the nephrons. Conclusion: Given the profound early mesenchymal expression and MET signature of LGR6+ cells, together with the lineage tracing of mesenchymal LGR6+ cells, we conclude that LGR6+ cells contribute to all nephrogenic segments by undergoing MET. LGR6+ cells can therefore be considered an early committed NPC population during embryonic and postnatal nephrogenesis with potential regenerative capability.

ORGANISM(S): Mus musculus

PROVIDER: GSE164795 | GEO | 2021/05/25

REPOSITORIES: GEO

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Project description:Bulk ATAC_seq on GFP expressing FACS-isolated cells from E16.5 and P0 Six2TGC and compound Ezh1 and Ezh2 mutant kidneys( Six2TGC_Ezh2-/- , Ezh1+/-; Six2TGC_Ezh2-/-; and Ezh1-/- ; scRNA-seq analysis of NPCs (Six2/GFP+ cells) from E16.5 as well as P2 kidneys. Genotypes analyzed: Six2TGC (E16.5&P2), Six2TGCEzh2-/- (E16.5), Ezh1+/-;Six2TGCEzh2-/- (E16.5), and Ezh2-/-;Six2TGCEzh2-/- (E16.5) Six2/GFP+ nephron progenitor cells (NPCs) give rise to all epithelial cell types of the nephron, the filtering unit of the kidney. NPCs have a limited lifespan and are consumed near the time of birth. Pre-term birth or prenatal stress further shorten the lifespan of NPCs and result in nephron deficit and chronic kidney disease. Accordingly, there is a pressing need to better understand the factors that regulate NPC lifespan in order to develop novel regenerative strategies. Epigenetic factors are implicated in maintenance of organ-restricted progenitors such as NPCs, but the chromatin-based mechanisms are not well understood. In this study, we examined the role of the H3K27 methyltransferases, Enhancer of zeste (Ezh1 and Ezh2), in NPC maintenance using a combination of gene targeting, chromatin profiling, and single-cell RNA analysis. We find that Ezh2 expression correlates with NPC growth potential, and that Ezh2 is the dominant H3K27 methyltransferase in NPCs and epithelial descendants. Surprisingly, NPCs lacking H3K27me3 maintain their progenitor state albeit cycle slowly leading to formation of fewer nephrons. Unlike Ezh2 loss-of-function, dual inactivation of Ezh1 and Ezh2 triggers overexpression of the transcriptional repressor Hey1 and downregulation of Six2 and result in unscheduled activation of Wnt4-driven differentiation, early termination of nephrogenesis and severe renal dysgenesis. Double-mutant NPCs also overexpress the Six family member, Six1. However, in this context, Six1 is unable to access the closed Six2 enhancer and fails to maintain NPC stemness. At the chromatin level, Ezh1 and Ezh2 act by restricting accessibility of AP1 factors to their genomic binding motifs and their absence provokes a regulatory landscape akin of differentiated and non-lineage cells. We conclude that Ezh2 is required for NPC renewal potential, while maintenance of NPC lifespan and tempering the differentiation program require cooperation of both Ezh1 and Ezh2.

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LGR6 marks nephron progenitor cells

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