Glial Orchestrated Neurodegeneration: An Important Crossroad for Neural Stem Cell Therapy to the Intestine

Figure 1. Neuronal-glia ineractions during intestinal inflammation and neural stem cell transfer. ATP, adenosine triphosphate; NO, nitric oxide; P2X7R, purinergic receptor P2X, ligand gated ion channel, 7. Cneurons in the human body. For more than a century, physicians and scientists have argued that glia provide the fundamental infrastructure and life support to neurons, without which the brain and intestine rapidly transcend into chaos. But what if popular consensus is wrong and our glial chaperones secretly monitor for epigenetic clues that determine whether a neuron will live or die? In this issue of Cellular and Molecular Gastroenterology and Hepatology, 2 independent reports provide new mechanistic insight into how enteric neurons survive during intestinal inflammation and after neural stem cell therapy. Both studies pose interesting and immediate questions about the rationale for intestinal autologous neural transplantation, which generally assumes that host immune function is the biggest adversary to prolonged neural stem cell survival in the enteric nervous system. Enteric neuropathy is associated with wide-ranging intestinal pathology and dysmotility: epitomized by inflammatory bowel disease and aganglionic bowel failure in Hirschsprung’s disease when embryonic neural crest cells fail to colonize the distal colon. Autologous neural stem cells are actively being explored as clinical therapy for Hirschsprung’s disease and hold much promise based on treatment successes already reported for hematopoietic and cardiac disease. Unlike allogenic stem cell therapy in which the recipient and donor are different people, autologous transplantation removes, expands, and later gives back stem cells to the same person to avoid immune rejection. In a mechanistic proof-of-concept study, Rollo et al significantly advance our understanding of potential barriers to autologous enteric neural therapy by showing that p75þ stem cells can be isolated and cultured from postnatal Hirschsprung’s colon using simulated Wnt-driven signaling. Importantly, expanded enteric neural stem cells retain the capacity to proliferate and colonize avian embryonic intestine, as well as postnatal aganglionic colon muscle cultures from the same patient. The investigators also confirm earlier reports that aneuronal colonic tissues from Hirschsprung’s patients harbor a rich network of neuronal precursors and glia. These findings are encouraging because they show in vitro feasibility for postnatal autologous neural cell transfer in Hirschsprung’s patients, but raise new questions. Are functional synapses formed in postnatal intestine after autologous neural stem cell transfer? Are non-neural cells in neurosphere cultures required for stem cell expansion? What is the origin of neural precursors and glia identified in aneuronal colon from Hirschsprung’s patients? Sacral neural crest and glial stem cells are potential alternative neural sources, but why do these precursors not differentiate in the