A branching model of lineage differentiation underpinning the neurogenic potential of enteric glia (Single-cell ATAC-seq data for enteric glial cells)

Glial cells have been proposed as an endogenous source of progenitors for the treatment of neural deficits. However, the cellular and molecular mechanisms underpinning the neurogenic potential of certain populations of adult glial cells, are not known. Using single cell transcriptomic profiling, we show here that enteric glial cells represent a cell state attained by autonomic neural crest cells as they transition during development along a linear default differentiation trajectory that allows them to retain neurogenic potential while acquiring a gene expression profile associated with their role in neuronal support and immunomodulation. Key neurogenic loci in early enteric nervous system progenitors remain in open chromatin configuration in mature enteric glia, thus facilitating neuronal differentiation under appropriate conditions. Molecular profiling and gene targeting of enteric glial cells in a novel cell culture system of enteric neurogenesis and a gut injury model, demonstrated that neuronal differentiation of glia is driven by transcriptional programs employed in vivo by early progenitors. Our work provides mechanistic insight into the dynamic regulatory landscape underpinning the development of intestinal neural circuits and generates a platform for advancing glial cells as therapeutic agents for the treatment of neural deficits. Overall design: We performed scATAC-seq of nGFP+ cells isolated from tunica muscularis preparations from 8 week old Sox10CreERT2(SER93);Rosa26-nuclearGFP mice that had been injected with tamoxifen (2 doses of tamoxifen at 100 µg/g of body weight 10 days prior isolation).