Enteric Nervous System Cell Replacement Therapy for Hirschsprung Disease: Beyond Tissue-Engineered Intestine

Abstract

Hirschsprung disease (HD), a neurocristopathy characterized by failed migration of neural crest cells to the distal colon, requires surgical resection of the aganglionic segment. Advances in stem cell and regenerative medicine research have opened the possibility to treat HD less invasively using enteric nervous system (ENS) cell replacement therapy. This article reviews the progress to date of culturing and delivering ENS stem cells in various in vitro and in vivo models, as well as review the available evidence of functionality of the transplant-derived cells. Potential areas of future study are identified, and application of conditions other than HD is briefly discussed.

Keywords

Hirschsprung disease - enteric nervous system stem cells - neurospheres - tissue-engineered colon - dysganglionosis

• References

• 1 Le Douarin NM, Teillet MA. The migration of neural crest cells to the wall of the digestive tract in avian embryo. J Embryol Exp Morphol 1973; 30 (1) 31-48
• 2 Heanue TA, Pachnis V. Enteric nervous system development and Hirschsprung's disease: advances in genetic and stem cell studies. Nat Rev Neurosci 2007; 8 (6) 466-479
• 3 Swenson O. A new surgical treatment for Hirschsprung's disease. Surgery 1950; 28 (2) 371-383
• 4 Yanchar NL, Soucy P. Long-term outcome after Hirschsprung's disease: patients' perspectives. J Pediatr Surg 1999; 34 (7) 1152-1160
• 5 Rintala RJ, Pakarinen MP. Long-term outcomes of Hirschsprung's disease. Semin Pediatr Surg 2012; 21 (4) 336-343
• 6 Vieten D, Spicer R. Enterocolitis complicating Hirschsprung's disease. Semin Pediatr Surg 2004; 13 (4) 263-272
• 7 Kruger GM, Mosher JT, Bixby S, Joseph N, Iwashita T, Morrison SJ. Neural crest stem cells persist in the adult gut but undergo changes in self-renewal, neuronal subtype potential, and factor responsiveness. Neuron 2002; 35 (4) 657-669
• 8 Belkind-Gerson J, Carreon-Rodriguez A, Benedict LA , et al. Nestin-expressing cells in the gut give rise to enteric neurons and glial cells. Neurogastroenterol Motil 2013; 25 (1) 61-67 , e7
• 9 Metzger M, Caldwell C, Barlow AJ, Burns AJ, Thapar N. Enteric nervous system stem cells derived from human gut mucosa for the treatment of aganglionic gut disorders. Gastroenterology 2009; 136 (7) 2214-2225 , e1–e3
• 10 Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992; 255 (5052) 1707-1710
• 11 Chojnacki A, Weiss S. Production of neurons, astrocytes and oligodendrocytes from mammalian CNS stem cells. Nat Protoc 2008; 3 (6) 935-940
• 12 Micci MA, Kahrig KM, Simmons RS, Sarna SK, Espejo-Navarro MR, Pasricha PJ. Neural stem cell transplantation in the stomach rescues gastric function in neuronal nitric oxide synthase-deficient mice. Gastroenterology 2005; 129 (6) 1817-1824
• 13 Micci MA, Learish RD, Li H, Abraham BP, Pasricha PJ. Neural stem cells express RET, produce nitric oxide, and survive transplantation in the gastrointestinal tract. Gastroenterology 2001; 121 (4) 757-766
• 14 Dong YL, Liu W, Gao YM , et al. Neural stem cell transplantation rescues rectum function in the aganglionic rat. Transplant Proc 2008; 40 (10) 3646-3652
• 15 Bondurand N, Natarajan D, Thapar N, Atkins C, Pachnis V. Neuron and glia generating progenitors of the mammalian enteric nervous system isolated from foetal and postnatal gut cultures. Development 2003; 130 (25) 6387-6400
• 16 Almond S, Lindley RM, Kenny SE, Connell MG, Edgar DH. Characterisation and transplantation of enteric nervous system progenitor cells. Gut 2007; 56 (4) 489-496
• 17 Lindley RM, Hawcutt DB, Connell MG , et al. Human and mouse enteric nervous system neurosphere transplants regulate the function of aganglionic embryonic distal colon. Gastroenterology 2008; 135 (1) 205-216 , e6
• 18 Rauch U, Hänsgen A, Hagl C, Holland-Cunz S, Schäfer K-H. Isolation and cultivation of neuronal precursor cells from the developing human enteric nervous system as a tool for cell therapy in dysganglionosis. Int J Colorectal Dis 2006; 21 (6) 554-559
• 19 Schäfer KH, Hagl CI, Rauch U. Differentiation of neurospheres from the enteric nervous system. Pediatr Surg Int 2003; 19 (5) 340-344
• 20 Metzger M, Bareiss PM, Danker T , et al. Expansion and differentiation of neural progenitors derived from the human adult enteric nervous system. Gastroenterology 2009; 137 (6) 2063-2073 , e4
• 21 Hotta R, Stamp LA, Foong JP , et al. Transplanted progenitors generate functional enteric neurons in the postnatal colon. J Clin Invest 2013; 123 (3) 1182-1191
• 22 Natarajan D, Grigoriou M, Marcos-Gutierrez CV, Atkins C, Pachnis V. Multipotential progenitors of the mammalian enteric nervous system capable of colonising aganglionic bowel in organ culture. Development 1999; 126 (1) 157-168
• 23 Martucciello G, Brizzolara A, Favre A , et al. Neural crest neuroblasts can colonise aganglionic and ganglionic gut in vivo. Eur J Pediatr Surg 2007; 17 (1) 34-40
• 24 Tsai YH, Murakami N, Gariepy CE. Postnatal intestinal engraftment of prospectively selected enteric neural crest stem cells in a rat model of Hirschsprung disease. Neurogastroenterol Motil 2011; 23 (4) 362-369
• 25 Anitha M, Joseph I, Ding X , et al. Characterization of fetal and postnatal enteric neuronal cell lines with improvement in intestinal neural function. Gastroenterology 2008; 134 (5) 1424-1435
• 26 Pan WK, Zheng BJ, Gao Y, Qin H, Liu Y. Transplantation of neonatal gut neural crest progenitors reconstructs ganglionic function in benzalkonium chloride-treated homogenic rat colon. J Surg Res 2011; 167 (2) e221-e230
• 27 Menezes M, Puri P. Long-term outcome of patients with enterocolitis complicating Hirschsprung's disease. Pediatr Surg Int 2006; 22 (4) 316-318
• 28 Barthel ER, Levin DE, Speer AL , et al. Human tissue-engineered colon forms from postnatal progenitor cells: an in vivo murine model. Regen Med 2012; 7 (6) 807-818
• 29 Spurrier RG, Grikscheit TC. Tissue engineering the small intestine. Clin Gastroenterol Hepatol 2013; 11 (4) 354-358
• 30 Grikscheit TC, Ochoa ER, Ramsanahie A , et al. Tissue-engineered large intestine resembles native colon with appropriate in vitro physiology and architecture. Ann Surg 2003; 238 (1) 35-41
• 31 Sala FG, Matthews JA, Speer AL, Torashima Y, Barthel ER, Grikscheit TC. A multicellular approach forms a significant amount of tissue-engineered small intestine in the mouse. Tissue Eng Part A 2011; 17 (13-14) 1841-1850
• 32 Levin DE, Barthel ER, Speer AL , et al. Human tissue-engineered small intestine forms from postnatal progenitor cells. J Pediatr Surg 2013; 48 (1) 129-137
• 33 Sala FG, Kunisaki SM, Ochoa ER, Vacanti J, Grikscheit TC. Tissue-engineered small intestine and stomach form from autologous tissue in a preclinical large animal model. J Surg Res 2009; 156 (2) 205-212
• 34 Speer AL, Sala FG, Matthews JA, Grikscheit TC. Murine tissue-engineered stomach demonstrates epithelial differentiation. J Surg Res 2011; 171 (1) 6-14
• 35 Grikscheit T, Ochoa ER, Srinivasan A, Gaissert H, Vacanti JP. Tissue-engineered esophagus: experimental substitution by onlay patch or interposition. J Thorac Cardiovasc Surg 2003; 126 (2) 537-544
• 36 Furness JB. The Enteric Nervous System. Oxford: Blackwell; 2006
• 37 Furness JB. The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol 2012; 9 (5) 286-294
• 38 Furness JB, Rivera LR, Cho HJ, Bravo DM, Callaghan B. The gut as a sensory organ. Nat Rev Gastroenterol Hepatol 2013; 10 (12) 729-740
• 39 Neunlist M, Van Landeghem L, Mahé MM, Derkinderen P, des Varannes SB, Rolli-Derkinderen M. The digestive neuronal-glial-epithelial unit: a new actor in gut health and disease. Nat Rev Gastroenterol Hepatol 2013; 10 (2) 90-100
• 40 Lindley RM, Hawcutt DB, Connell MG, Edgar DH, Kenny SE. Properties of secondary and tertiary human enteric nervous system neurospheres. J Pediatr Surg 2009; 44 (6) 1249-1255 , discussion 1255–1256
• 41 Zhou Y, Yang J, Watkins DJ , et al. Enteric nervous system abnormalities are present in human necrotizing enterocolitis: potential neurotransplantation therapy. Stem Cell Res Ther 2013; 4 (6) 157
• 42 De Giorgio R, Giancola F, Boschetti E, Abdo H, Lardeux B, Neunlist M. Enteric glia and neuroprotection: basic and clinical aspects. Am J Physiol Gastrointest Liver Physiol 2012; 303 (8) G887-G893
• 43 Mosher JT, Yeager KJ, Kruger GM , et al. Intrinsic differences among spatially distinct neural crest stem cells in terms of migratory properties, fate determination, and ability to colonize the enteric nervous system. Dev Biol 2007; 303 (1) 1-15