Integrated single-cell analysis of enteric glial cells reveals a molecular basis for postnatal neurogenesis and its therapeutic application

Abstract

The enteric nervous system (ENS) consists of glial cells (EGCs) and neurons derived from neural crest precursors. EGCs retain capacity for large-scale neurogenesis in culture, and in vivo lineage tracing has identified neurons derived from glial cells in response to inflammation. We thus hypothesize that EGCs possess a chromatin structure poised for neurogenesis. We use single-cell multiome sequencing to assess EGCs undergoing spontaneous neurogenesis in culture, as well as freshly isolated small intestine myenteric plexus EGCs. Cultured EGCs maintain open chromatin at genomic loci accessible in neurons, and neurogenesis from EGCs involves dynamic chromatin rearrangements with a net decrease in accessible chromatin. Multiome analysis of freshly isolated EGCs reveals transcriptional diversity, with open chromatin at neuron-associated genomic elements. A subset of EGCs, highly enriched within the myenteric ganglia, has a gene expression program and chromatin state consistent with neurogenic potential.