Abstract
Putative neural stem cells have been identified within the enteric nervous system (ENS) of adult rodents and cultured from human myenteric plexus. We conducted studies to identify neural stem cells or progenitor cells within the submucosa of adult human ENS. Jejunum tissue was removed from adult human subjects undergoing gastric bypass surgery. The tissue was immunostained, and confocal images of ganglia in the submucosal plexus were collected to identify protein gene product 9.5 (PGP 9.5) - immunoractive neurons and neuronal progenitor cells that coexpress PGP 9.5 and nestin. In addition to PGP-9.5-positive/nestin-negative neuronal cells within ganglia, we observed two other types of cells: (1) cells in which PGP 9.5 and nestin were co-localized, (2) cells negative for both PGP 9.5 and nestin. These observations suggest that the latter two types of cells are related to a progenitor cell population and are consistent with the concept that the submucosa of human adult ENS contains stem cells capable of maintenance and repair within the peripheral nervous system.
References
Chalazonitis A, Rothman TP, Chen J, Gershon MD (1998) Age-dependent differences in the effects of GDNF and NT-3 on the development of neurons and glia from neural crest-derived precursors immunoselected from the fetal rat gut: expression of GFRalpha-1 in vitro and in vivo. Dev Biol 204:385–406
Dupin E, Creuzet S, Le Douarin NM (2006) The contribution of the neural crest to the vertebrate body. Adv Exp Med Biol 589:96–119
Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317
Faure C, Chalazonitis A, Rheaume C, Bouchard G, Gopalan Sampathkumar S, Yarema KJ, Gershon MD (2007) Gangliogenesis in the enteric nervous system: roles of the polysialylation of the neural cell adhesion molecule and its regulation by bone morphogenetic protein-4. Dev Dyn 236:44–59
Ferri GL, Probert L, Cocchia D, Michetti F, Marangos PJ, Polak JM (1982) Evidence for the presence of S-100 protein in the glial component of the human enteric nervous system. Nature 297:409–410
Furness JB (2000) Types of neurons in the enteric nervous system. J Auton Nerv Syst 81:87–96
Hanani M, Ledder O, Yutkin V, Abu-Dalu R, Huang TY, Härtig W, Vannucchi MG, Faussone-Pellegrini MS (2003) Regeneration of myenteric plexus in the mouse colon after experimental denervation with benzalkonium chloride. J Comp Neurol 462:315–327
Jiang Y, Liu M, Gershon MD (2003) Netrins and DCC in the guidance of migrating neural crest-derived cells in the developing bowel and pancreas. Dev Biol 258:364–384
Kruger GM, Mosher JT, Bixby S, Joseph N, Iwashita T, Morrison SJ (2002) Neural crest stem cells persist in the adult gut but undergo changes in self-renewal, neuronal subtype potential, and factor responsiveness. Neuron 35:657–669
Kukekov VG, Laywell ED, Thomas LB, Steindler DA (1997) A nestin-negative precursor cell from the adult mouse brain gives rise to neurons and glia. Glia 21:399–407
Lendahl U, Zimmerman LB, McKay RD (1990) CNS stem cells express a new class of intermediate filament protein. Cell 60:585–595
Lo L, Anderson DJ (1995) Postmigratory neural crest cells expressing c-ret display restricted developmental and proliferative capacities. Neuron 15:527–539
McKeown SJ, Chow CW, Young HM (2001) Development of the submucous plexus in the large intestine of the mouse. Cell Tissue Res 303:301–305
Messam CA, Hou J, Major EO (2000) Coexpression of nestin in neural and glial cells in the developing human CNS defined by a human-specific anti-nestin antibody. Exp Neurol 161:585–596
Metzger M, Caldwell C, Barlow AJ, Burns AJ, Thapar N (2009a) Enteric nervous system stem cells derived from human gut mucosa for the treatment of aganglionic gut disorders. Gastroenterology 136:2214–2225
Metzger M, Bareiss PM, Danker T, Wagner S, Hennenlotter J, Guenther E, Obermayr F, Stenzl A, Koenigsrainer A, Skutella T, Just L (2009b) Expansion and differentiation of neural progenitors derived from the human adult enteric neurvous system. Gastroenterology 137:2063–2073
Metzger M (2010) Neurogenesis in the enteric nervous system. Arch Ital Biol 148:73–83
Quiñones-Hinojosa A, Sanai N, Soriano-Navarro M, Gonzalez-Perez O, Mirzadeh Z, Gil-Perotin S, Romero-Rodriguez R, Berger MS, Garcia-Verdugo JM, Alvarez-Buylla (2006) Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells. J Comp Neurol 494:415–434
Rauch U, Hänsgen A, Hagl C, Holland-Cunz S, Schäfer KH (2006a) 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 21:554–559
Rauch U, Klotz M, Maas-Omlor S, Wink E, Hansgen A, Hagl C, Holland-Cunz S, Schäfer KH (2006b) Expression of intermediate filament proteins and neuronal markers in the human fetal gut. J Histochem Cytochem 54:39–46
Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710
Rothman TP, Le Douarin NM, Fontaine-Perus JC, Gershon MD (1993) Colonization of the bowel by neural crest-derived cells re-migrating from foregut back transplanted to vagal or sacral regions of host embryos. Dev Dyn 196:217–233
Sakurai M, Ayukawa K, Setsuie R, Nishikawa K, Hara Y, Ohashi H, Nishimoto M, Abe T, Kudo Y, Sekiguchi M, Sato Y, Aoki S, Noda M, Wada K (2006) Ubiquitin C-terminal hydrolase L1 regulates the morphology of neural progenitor cells and modulates their differentiation. J Cell Sci 119:162–167
Schäfer K-H, Hagl CI, Rauch U (2003) Differentiation of neurospheres from the enteric nervous system. Pediatr Surg Int 19:340–344
Schäfer K-H, Ginneken CV, Copray S (2009) Plasticity and neural stem cells in the enteric nervous system. Anat Rec 292:1940–1952
Schofield JN, Day IN, Thompson RJ, Edwards YH (1995) PGP9.5, a ubiquitin C-terminal hydrolase; pattern of mRNA and protein expression during neural development in the mouse. Dev Brain Res 85:229–238
Shi H, Cui H, Alam G, Gunning WT, Nestor A, Giovannucci D, Zhang M, Ding HF (2008) Nestin expression defines both glial and neuronal progenitors in postnatal sympathetic ganglia. J Comp Neurol 508:867–878
Sidebotham EL, Woodward MN, Kenny SE, Lloyd DA, Vaillant CR, Edgar DH (2001) Assessment of protein gene product 9.5 as a marker of neural crest-derived precursor cells in the developing enteric nervous system. Pediatr Surg Int 17:304–307
Silva AT, Wardhaugh T, Dolatshad NF, Jones S, Saffrey MJ (2008) Neural progenitors from isolated postnatal rat myenteric ganglia: expansion as neurospheres and differentiation in vitro. Brain Res 1218:47–53
Stemple DL, Anderson DJ (1992) Isolation of a stem cell for neurons and glia from the mammalian neural crest. Cell 71:973–985
Suárez-Rodríguez R, Belkind-Gerson J (2004) Cultured nestin-positive cells from postnatal mouse small bowel differentiate ex vivo into neurons, glia, and smooth muscle. Stem Cells 22:1373–1385
Sukegawa A, Narita T, Kameda T, Saitoh K, Nohno T, Iba H, Yasugi S, Fukuda K (2000) The concentric structure of the developing gut is regulated by sonic hedgehog derived from endodermal epithelium. Development 127:1971–1980
Vanderwinden JK, Gillard K, De Laet MH, Messam CA, Schiffmann SN (2002) Distribution of the intermediate filament nestin in the muscularis propria of the human gastrointestinal tract. Cell Tissue Res 309:261–268
Young HM, Bergner AJ, Müller T (2003) Acquisition of neuronal and glial markers by neural crest-derived cells in the mouse intestine. J Comp Neurol 456:1–11
Young HM, Turner KN, Bergner AJ (2005) The location and phenotype of proliferating neural-crest-derived cells in the developing mouse gut. Cell Tissue Res 320:1–9
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The authors thank the Juvenile Diabetes Research Foundation for supporting research on the enteric nervous system.
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Azan, G., Low, W.C., Wendelschafer-Crabb, G. et al. Evidence for neural progenitor cells in the human adult enteric nervous system. Cell Tissue Res 344, 217–225 (2011). https://doi.org/10.1007/s00441-011-1130-9
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DOI: https://doi.org/10.1007/s00441-011-1130-9