Metabolic and mechanical coupling of enteric nervous system in regenerating colon

Abstract

Resolution of inflammation in different tissues still remains unclear. Different cell types coordinate to ameliorate inflammatory regions. In colon, enteric nervous system (ENS) is one of cell types that responds to inflammation with its heterogeneous cell types and locations throughout different layers. However, reaction of enteric glia and neuron to regeneration mechanistically and metabolically is still unknown. In this study, we found that neurons are hyperactivated upon inflammation and produce lipid droplets; enteric glia uptake these lipids to protect neurons from lipid induced toxicity. Lipid particles are stored in enteric glia. In addition to metabolic response, there is also metabolic response of ENS to regeneration which is resolved by spatial transcriptomics. This method enabled us to identify transcripts in their exact positions on the tissue; allowed us to determine transcript proximities to each other in a reorganizing tissue. We found that PTN-PTPRZ1 axis is a regulator of cell inclination of ENS cells in muscularis externa towards the submucosa. Co-expression of Ptn-Ptprz1 was increased in the regenerative area of the colon. Moreover, to determine role of ENS in tissue reorientation in vitro, we achieved to produce ENS harboring complex assembloids. Enteric progenitor cells derived neuron and glia cells from muscularis externa were able to migrate mucosa. This study underscores diverse aspects of ENS cells to aid regeneration process upon regeneration in colon.