Isolation, Expansion and Transplantation of Postnatal Murine Progenitor Cells of the Enteric Nervous System

Neural stem or progenitor cells have been proposed to restore gastrointestinal function in patients suffering from congenital or acquired defects of the enteric nervous system. Various, mainly embryonic cell sources have been identified for this purpose. However, immunological and ethical issues make a postnatal cell based therapy desirable. We therefore evaluated and quantified the potential of progenitor cells of the postnatal murine enteric nervous system to give rise to neurons and glial cells in vitro. Electrophysiological analysis and BrdU uptake studies provided direct evidence that generated neurons derive from expanded cells in vitro. Transplantation of isolated and expanded postnatal progenitor cells into the distal colon of adult mice demonstrated cell survival for 12 weeks (end of study). Implanted cells migrated within the gut wall and differentiated into neurons and glial cells, both of which were shown to derive from proliferated cells by BrdU uptake. This study indicates that progenitor cells isolated from the postnatal enteric nervous system might have the potential to serve as a source for a cell based therapy for neurogastrointestinal motility disorders. However, further studies are necessary to provide evidence that the generated cells are capable to positively influence the motility of the diseased gastrointestinal tract.

[1]  D. Newgreen,et al.  Transplanted progenitors generate functional enteric neurons in the postnatal colon. , 2013, The Journal of clinical investigation.

[2]  Benjamin M. Wu,et al.  Transplantation of enteric cells into the aganglionic rodent small intestines. , 2012, The Journal of surgical research.

[3]  Benjamin M. Wu,et al.  Transplantation of enteric cells expressing p75 in the rodent stomach. , 2012, The Journal of surgical research.

[4]  J. Bornstein,et al.  Early Emergence of Neural Activity in the Developing Mouse Enteric Nervous System , 2011, The Journal of Neuroscience.

[5]  K. Krogh Gastrointestinal Dysfunction in Parkinson’s Disease , 2011 .

[6]  Ya Gao,et al.  Transplantation of neonatal gut neural crest progenitors reconstructs ganglionic function in benzalkonium chloride-treated homogenic rat colon. , 2011, The Journal of surgical research.

[7]  C. Gariepy,et al.  Postnatal intestinal engraftment of prospectively selected enteric neural crest stem cells in a rat model of Hirschsprung disease , 2011, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[8]  M. Pakarinen,et al.  Bowel Function and Gastrointestinal Quality of Life Among Adults Operated for Hirschsprung Disease During Childhood: A Population-Based Study , 2010, Annals of surgery.

[9]  H. Parkman,et al.  Gastric Neuromuscular Pathology in Gastroparesis: Analysis of Full-Thickness Antral Biopsies , 2010, Digestive Diseases and Sciences.

[10]  A. Stenzl,et al.  Expansion and differentiation of neural progenitors derived from the human adult enteric nervous system. , 2009, Gastroenterology.

[11]  D. Natarajan,et al.  Potential of cell therapy to treat pediatric motility disorders. , 2009, Seminars in pediatric surgery.

[12]  A. Burns,et al.  Enteric nervous system stem cells derived from human gut mucosa for the treatment of aganglionic gut disorders. , 2009, Gastroenterology.

[13]  P. Pasricha,et al.  Neural stem cell transplantation in the enteric nervous system: roadmaps and roadblocks , 2009, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[14]  H. Wang,et al.  Neural stem cell transplantation rescues rectum function in the aganglionic rat. , 2008, Transplantation proceedings.

[15]  M. Vannucchi,et al.  Human and mouse enteric nervous system neurosphere transplants regulate the function of aganglionic embryonic distal colon. , 2008, Gastroenterology.

[16]  S. Hochman,et al.  Characterization of fetal and postnatal enteric neuronal cell lines with improvement in intestinal neural function. , 2008, Gastroenterology.

[17]  Y. Gao,et al.  Neuroepithelial stem cells differentiate into neuronal phenotypes and improve intestinal motility recovery after transplantation in the aganglionic colon of the rat , 2007, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[18]  V. Pachnis,et al.  Enteric nervous system development and Hirschsprung's disease: advances in genetic and stem cell studies , 2007, Nature Reviews Neuroscience.

[19]  M. Gershon Transplanting the enteric nervous system: a step closer to treatment for aganglionosis , 2007, Gut.

[20]  R. Bocciardi,et al.  Neural crest neuroblasts can colonise aganglionic and ganglionic gut in vivo. , 2007, European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie.

[21]  M. Metzger,et al.  Three‐dimensional slice cultures from murine fetal gut for investigations of the enteric nervous system , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[22]  D. Edgar,et al.  Characterisation and transplantation of enteric nervous system progenitor cells , 2006, Gut.

[23]  S. Holland-Cunz,et al.  Isolation and cultivation of neuronal precursor cells from the developing human enteric nervous system as a tool for cell therapy in dysganglionosis , 2006, International Journal of Colorectal Disease.

[24]  P. Pasricha,et al.  Neural stem cell transplantation in the stomach rescues gastric function in neuronal nitric oxide synthase-deficient mice. , 2005, Gastroenterology.

[25]  M. Schemann Control of gastrointestinal motility by the "gut brain"--the enteric nervous system. , 2005, Journal of pediatric gastroenterology and nutrition.

[26]  J. Belkind-Gerson,et al.  Cultured Nestin–Positive Cells from Postnatal Mouse Small Bowel Differentiate Ex Vivo into Neurons, Glia, and Smooth Muscle , 2004, Stem cells.

[27]  J. Wood,et al.  Enteric neuroimmunophysiology and pathophysiology. , 2004, Gastroenterology.

[28]  C. Gariepy Developmental Disorders of the Enteric Nervous System: Genetic and Molecular Bases , 2004, Journal of pediatric gastroenterology and nutrition.

[29]  P. Wade,et al.  Neurodegeneration: a key factor in the ageing gut , 2004, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[30]  P. Pasricha,et al.  Enteric neural crest‐derived cells and neural stem cells: biology and therapeutic potential , 2004, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[31]  C. Atkins,et al.  Neuron and glia generating progenitors of the mammalian enteric nervous system isolated from foetal and postnatal gut cultures , 2003, Development.

[32]  R. Pfeiffer Gastrointestinal dysfunction in Parkinson's disease. , 2011, Parkinsonism & related disorders.

[33]  S. Morrison,et al.  Neural Crest Stem Cells Persist in the Adult Gut but Undergo Changes in Self-Renewal, Neuronal Subtype Potential, and Factor Responsiveness , 2002, Neuron.

[34]  D. Newgreen,et al.  Enteric Nervous System: Development and Developmental Disturbances—Part 2 , 2002, Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society.

[35]  D. Newgreen,et al.  Enteric Nervous System: Development and Developmental Disturbances—Part 1 , 2002, Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society.

[36]  Hui Li,et al.  Neural stem cells express RET, produce nitric oxide, and survive transplantation in the gastrointestinal tract. , 2001, Gastroenterology.

[37]  J. Furness Types of neurons in the enteric nervous system. , 2000, Journal of the autonomic nervous system.

[38]  M. Gershon,et al.  Activation of Intrinsic Afferent Pathways in Submucosal Ganglia of the Guinea Pig Small Intestine , 2000, The Journal of Neuroscience.

[39]  A. Reichenbach,et al.  Patch-clamp study of neurons and glial cells in isolated myenteric ganglia. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[40]  T. K. Smith,et al.  Diverse ionic currents and electrical activity of cultured myenteric neurons from the guinea pig proximal colon. , 2000, Journal of neurophysiology.

[41]  M. Gershon The enteric nervous system: a second brain. , 1999, Hospital practice.

[42]  P. Wade,et al.  The enteric nervous system. , 1981, Annual review of neuroscience.

[43]  C. L. Yntema,et al.  The origin of intrinsic ganglia of trunk viscera from vagal neural crest in the chick embryo , 1954, The Journal of comparative neurology.

[44]  A. Brehmer Structure of enteric neurons. , 2006, Advances in anatomy, embryology, and cell biology.

[45]  C. Atkins,et al.  Multipotential progenitors of the mammalian enteric nervous system capable of colonising aganglionic bowel in organ culture. , 1999, Development.