LGR6 marks nephron progenitor cells. Issue 11 (6th May 2021) - van Ineveld, Ravian L.
Abstract: Background: Nephron progenitor cells (NPCs) undergo a stepwise process to generate all mature nephron structures. Mesenchymal to epithelial transition (MET) is considered a multistep 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. Conclusions: 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. Key Findings: Lgr6 is expressed in the earliest cap mesenchyme pool, a niche where nephrogenic progenitor cells (NPCs) are found. Lgr6 marks NPCs undergoing mesenchymal to epithelial transition, following the main process of nephron development. Using ex vivo and vivo lineage tracing, we show that mesenchymal Lgr6 expressing cells give rise to multiple types of mesenchymal derived nephron segments, including specialized glomerular epithelium, such as podocytes.