Neural G0: a quiescent‐like state found in neuroepithelial‐derived cells and glioma

Abstract

Single‐cell RNA sequencing has emerged as a powerful tool for resolving cellular states associated with normal and maligned developmental processes. Here, we used scRNA‐seq to examine the cell cycle states of expanding human neural stem cells (hNSCs). From these data, we constructed a cell cycle classifier that identifies traditional cell cycle phases and a putative quiescent‐like state in neuroepithelial‐derived cell types during mammalian neurogenesis and in gliomas. The Neural G0 markers are enriched with quiescent NSC genes and other neurodevelopmental markers found in non‐dividing neural progenitors. Putative glioblastoma stem‐like cells were significantly enriched in the Neural G0 cell population. Neural G0 cell populations and gene expression are significantly associated with less aggressive tumors and extended patient survival for gliomas. Genetic screens to identify modulators of Neural G0 revealed that knockout of genes associated with the Hippo/Yap and p53 pathways diminished Neural G0 in vitro, resulting in faster G1 transit, down‐regulation of quiescence‐associated markers, and loss of Neural G0 gene expression. Thus, Neural G0 represents a dynamic quiescent‐like state found in neuroepithelial‐derived cells and gliomas.

Single-cell multiomics reveals heterogeneous cell states linked to metastatic potential in liver cancer cell lines

“…This suggested a gradual increase in proliferation capability in cell lines in the same order, which also aligned with increasing metastatic potential. This result was consistent with a previous study ( O'Connor et al., 2021 ) where the population of G0 cells was significantly associated with less aggressive tumors. This held true in our study, except for the Huh7 cell line, which had a median proliferation rate (G0: 0.19), but had the lowest metastatic potential.…”

How can same-gene mutations promote both cancer and developmental disorders?

“…Pathological and nonpathological brain cell type–specific profiles of the mRNA are critical ( 65 ), particularly in the striatum, an essential relay of motor, cognitive, and limbic processes, suggesting highly specific roles in cell subpopulations ( 66 ). This scenario is supported by analysis of the mRNA of brain cells, which observed gene expression changes linked to ASD ( 67 , 68 ) and other neurodevelopmental disorders, such as bipolar disorders ( 69 ). The phenotypes were associated with neurons in the upper layers of the cortex and microglial activation genes, and the developmental transcription factor genes were most affected ( 70 ).…”

“…If the number of molecules in a specific node is too low, pathway rewiring through involvement of transcription factor isoforms (or other factors) can take place, resulting in premature developmental senescence. One way for this blueprint to be tested is by the mRNA levels of the nodes in the specific cell ( 67 ).…”

KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma

“…Previous work has established that low grade gliomas (LGGs) exhibit more indolent growth compared to high grade gliomas (HGGs) (Eckel-Passow et al, 2015) and almost universally harbor IDH1/2 mutations (Parsons et al, 2008). Based on gene expression analysis, LGGs have a higher proportion of G0-like cells compared to HGGs (O'Connor et al, 2021). Although LGGs result in better responses to standard of care and extended survival times, they inevitably recur as HGG with IDH1/2 mut (Ohgaki and Kleihues, 2013).…”

“…To investigate the occurrence of G0 and other cell cycle states in glioma, we recently created a computational cell cycle classifier based on cellular states observed self-renewing human fetal NSC, which included a quiescent state dubbed Neural G0 (O’Connor et al, 2021). When applied to glioma scRNA-seq data, this classifier could identify putative G0-like cells and associated transcriptional networks.…”