A tale of two cousins: Ependymal cells, quiescent neural stem cells and potential mechanisms driving their functional divergence

Abstract

Recent work has suggested that stem cells exhibit far greater heterogeneity than initially thought. Indeed, their dynamic nature and shared traits with surrounding niche cells have made prospective identification of adult neural stem cells (NSCs) challenging. Refined fate mapping strategies and single‐cell omics techniques have begun to clarify functionally distinct states within the adult NSC pool, the molecular signatures that govern these states, and the functional contributions/interactions with neighboring cells within the subventricular niche. Ependymal cells are the epithelial cells which line the ventricular system and reside in the same niche as NSCs. Our own work has revealed that, despite sharing similar embryonic origins with NSCs and close geographic proximity, ependymal cells are transcriptionally distinct and fail to exhibit stem cell function in vivo, even following injury. Intriguingly, comparison of ependymal cells with qNSCs revealed transcriptional signatures that are largely overlapping, suggesting that post‐transcriptional regulation might underlie their divergent phenotypes. Additional analysis of ependymal versus qNSC gene regulatory network activation supports this notion. This Viewpoint summarizes the historical confusion regarding the identity of NSCs within the lateral ventricle niche and describes recent work that provides greater appreciation for the diverse functional states within the NSC niche.

Diversity of Adult Neural Stem and Progenitor Cells in Physiology and Disease

“…Contradicting results have been reported regarding the appropriate contribution of ependymal cells to the pathophysiology of SCI and TBI [91,95,96]. This discrepancy is attributed to major differences in CNS injury models, animal models, and quantification techniques [95,97]. Differences in injury models range from damage to the ependymal layer, gray, and white matter to no damage to the ependymal layer but exposure to injury mediators such as glutamate.…”

“…Intrinsic factors include transcription factor Foxj1 and nuclear factor IX (NFIX) [94]. Quiescence/survival is regulated by DNA-binding protein inhibitor (Id3) and HES family transcription factor 5 (Hes5) [97]. Proliferation is regulated by Wnt signaling and growth factors [100].…”

Diversity of Adult Neural Stem and Progenitor Cells in Physiology and Disease

“…Contradicting results have been reported regarding the appropriate contribution of ependymal cells to the pathophysiology of SCI and TBI [38,72,77,78]. This discrepancy is attributed to major differences in CNS injury models, animal models, and quantification techniques [77,79]. Differences in injury models range from damage to the ependymal layer, gray, and white matter to no damage to the ependymal layer but exposure to injury mediators such as glutamate.…”

“…Intrinsic factors include transcription factor Foxj1 and nuclear factor IX (NFIX) [76]. Quiescence/survival is regulated by DNAbinding protein inhibitor (Id3) and HES family transcription factor 5 (Hes5) [79]. Proliferation is regulated by Wnt signaling and growth factors [83].Differentiation is directed by the Geminin superfamily, an antagonist of DNA replication, and NFIX [84,85].…”

A novel stem cell type at the basal side of the subventricular zone maintains adult neurogenesis

“…To specifically downregulate Hes1 expression in the apical V-SVZ, we took advantage of intraventricular injection of adeno associated virus (AAV) constitutively expressing GFP and either a Hes1 specific short hairpin (AAV-Hes1-sh) or a scramble control (AAV-sc-sh) as described before (Luque-Molina et al 2019). With this approach, beside apical NSCs, we also target ependymal cells, which also express Hes-1 (Stratton et al 2019). Therefore, we used meta-analysis of the RNA-sequencing data collected and made available by the lab of Sten Linnarsson at Karolinska Institute, Sweden (Zeisel et al 2018), on mousebrain.org to investigate Hes-1 expression in ependymal cells ( Supplementary Fig.…”