Future Therapies for Enteric Nervous System Diseases

Ana Roibu

The enteric nervous system (ENS) is the biggest and most elaborate branch of the peripheral nervous system. It operates the gastrointestinal tract independently of the central nervous system, although they share some of the same neurotransmitters, such as acetylcholine, dopamine and serotonin. The ENS has more neurons than the spinal cord and more glial cells than neurons, with various diseases affecting it. The development of the ENS originates from neural crest cells, a group of multi-potent stem cells generated at the gastrulation phase between the neural and non-neural ectoderm. Many birth defects and developmental disorders originate due to abnormal neural crest development.

The most common developmental disease of the ENS is Hirschsprung’s disease, which is characterised by a lack of enteric ganglia (aganglionosis) in a variable length of the gastrointestinal tract. Neural crest cells (NCCs) fail to migrate, leading to aganglionosis, with the size and area equivalating to the time of migration arrest ). This often results in bowel obstruction and is treated through surgery. Various genes, as well as some environmental factors influence the developmental process of ENS diseases. Other developmental diseases of the ENS include neuropathies of different kinds and myenteric hypo/hyper aganglionosis. The future of stem cell transplantation and genetic editing is promising, as possible future therapeutic treatments could provide successful treatment.

Recent advances outline the possibility of cellular transplants as treatment in the future. ENS stem cell transplantation is a possible future treatment not only for Hirschsprung’s disease but also for other congenital ENS disorders. The use of both induced pluripotent stem cells (iPSCs) and somatic stem cells is a possibility in the future treatment of Hirschsprung’s disease. Genetic manipulation of cells might be necessary before transplantation, although more research needs to be conducted for this to become a possible treatment option. Recent studies have also noted the prospect of correcting the RET (long-segment Hirschsprung’s disease) or VCL (short-segment Hirschsprung’s disease) mutation in iPSCs to restore the function the ability of enteric neural crest cells differentiate and migrate. Using the CRISPR/Ca9 technique, corrections in iPSCs with either of the mutations have re-established the function of enteric neural crest cells.

Despite advances in research, certain crucial mechanisms are still poorly understood. More research is needed in order to fully understand the process which controls ENS precursor differentiation in the various separate neuron subtypes.

Edited by: Karen Yung