{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T00:12:47Z","timestamp":1785024767980,"version":"3.55.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2015,4,14]],"date-time":"2015-04-14T00:00:00Z","timestamp":1428969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Department of Defense Undersecretary of Health Affairs","award":["W81XWH-13-2-0052, GU 7"],"award-info":[{"award-number":["W81XWH-13-2-0052, GU 7"]}]},{"DOI":"10.13039\/100000062","name":"NIH\/National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK071614"],"award-info":[{"award-number":["R01DK071614"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title\/>\n                  <jats:p>Appendix-derived neural progenitor cells (NPCs) have both neurogenic and gliogenic potential, but use of these cells for enteric neural cell therapy has not been addressed. The objective of this study was to determine whether NPCs obtained from the appendix would differentiate into enteric neural subsets capable of inducing neurotransmitter-mediated smooth muscle cell (SMC) contraction and relaxation. NPCs were isolated from the appendix and small intestine (SI) of rabbits. Bioengineered internal anal sphincter constructs were developed using the same source of smooth muscle and innervated with NPCs derived from either the appendix or SI. Innervated constructs were assessed for neuronal differentiation markers through Western blots and immunohistochemistry, and functionality was assessed through force-generation studies. Expression of neural and glial differentiation markers was observed in constructs containing appendix- and SI-derived NPCs. The addition of acetylcholine to both appendix and SI constructs caused a robust contraction that was decreased by pretreatment with the neural inhibitor tetrodotoxin (TTX). Electrical field stimulation caused relaxation of constructs that was completely abolished in the presence of TTX and significantly reduced on pretreatment with nitric oxide synthase inhibitor (N\u03c9-nitro-l-arginine methyl ester hydrochloride [l-NAME]). These data indicate that in the presence of identical soluble factors arising from intestinal SMCs, enteric NPCs derived from the appendix and SI differentiate in a similar manner and are capable of responding to physiological stimuli. This coculture paradigm could be used to explore the nature of the soluble factors derived from SMCs and NPCs in generating specific functional innervations.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>This study demonstrates the ability of neural stem cells isolated from the appendix to differentiate into mature functional enteric neurons. The differentiation of neural stem cells from the appendix is similar to differentiation of neural stem cells derived from the gastrointestinal tract. The appendix is a vestigial organ that can be removed with minimal clinical consequence through laparoscopy. Results presented in this paper indicate that the appendix is a potential source of autologous neural stem cells required for cell therapy for the gastrointestinal tract.<\/jats:p>\n               <\/jats:sec>","DOI":"10.5966\/sctm.2014-0238","type":"journal-article","created":{"date-parts":[[2015,4,15]],"date-time":"2015-04-15T01:22:24Z","timestamp":1429060944000},"page":"548-554","source":"Crossref","is-referenced-by-count":10,"title":["The Appendix as a Viable Source of Neural Progenitor Cells to Functionally Innervate Bioengineered Gastrointestinal Smooth Muscle Tissues"],"prefix":"10.1093","volume":"4","author":[{"given":"Elie","family":"Zakhem","sequence":"first","affiliation":[{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA"},{"name":"Department of Molecular Medicine and Translational Science, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L.","family":"Rego","sequence":"additional","affiliation":[{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreya","family":"Raghavan","sequence":"additional","affiliation":[{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA"},{"name":"Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Winston-Salem, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalil N.","family":"Bitar","sequence":"additional","affiliation":[{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA"},{"name":"Department of Molecular Medicine and Translational Science, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA"},{"name":"Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Winston-Salem, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,4,14]]},"reference":[{"key":"2021122704233629000_R1","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev.ne.04.030181.001303","article-title":"The enteric nervous system","volume":"4","author":"Gershon","year":"1981","journal-title":"Annu Rev Neurosci"},{"key":"2021122704233629000_R2","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.tins.2010.06.002","article-title":"Developmental determinants of the independence and complexity of the enteric nervous system","volume":"33","author":"Gershon","year":"2010","journal-title":"Trends Neurosci"},{"key":"2021122704233629000_R3","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.autneu.2003.09.001","article-title":"Multiple myenteric networks in the human appendix","volume":"110","author":"Hanani","year":"2004","journal-title":"Auton Neurosci"},{"key":"2021122704233629000_R4","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/0016-5085(86)90869-3","article-title":"Integrity of cholinergic innervation to the lower esophageal sphincter in achalasia","volume":"90","author":"Holloway","year":"1986","journal-title":"Gastroenterology"},{"key":"2021122704233629000_R5","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1016\/S0002-9270(99)00413-X","article-title":"Esophageal and gastric nitric oxide synthesizing innervation in primary achalasia","volume":"94","author":"De Giorgio","year":"1999","journal-title":"Am J Gastroenterol"},{"key":"2021122704233629000_R6","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1097\/00005176-199501000-00010","article-title":"Absence of NADPH-diaphorase activity in internal anal sphincter (IAS) achalasia","volume":"20","author":"Hirakawa","year":"1995","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"2021122704233629000_R7","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nrgastro.2013.226","article-title":"Neural stem cell therapies for enteric nervous system disorders","volume":"11","author":"Burns","year":"2014","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2021122704233629000_R8","doi-asserted-by":"crossref","first-page":"2063.e4","DOI":"10.1053\/j.gastro.2009.06.038","article-title":"Expansion and differentiation of neural progenitors derived from the human adult enteric nervous system","volume":"137","author":"Metzger","year":"2009","journal-title":"Gastroenterology"},{"key":"2021122704233629000_R9","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1023\/A:1005581531603","article-title":"Reaggregation of rat dissociated myenteric plexus in extracellular matrix gels","volume":"45","author":"Sch\u00e4fer","year":"2000","journal-title":"Dig Dis Sci"},{"key":"2021122704233629000_R10","doi-asserted-by":"crossref","first-page":"7429","DOI":"10.1016\/j.biomaterials.2014.05.037","article-title":"The influence of extracellular matrix composition on the differentiation of neuronal subtypes in tissue engineered innervated intestinal smooth muscle sheets","volume":"35","author":"Raghavan","year":"2014","journal-title":"Biomaterials"},{"key":"2021122704233629000_R11","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1016\/j.biomaterials.2013.11.049","article-title":"Neo-innervation of a bioengineered intestinal smooth muscle construct around chitosan scaffold","volume":"35","author":"Zakhem","year":"2014","journal-title":"Biomaterials"},{"key":"2021122704233629000_R12","doi-asserted-by":"crossref","first-page":"6649","DOI":"10.1016\/j.biomaterials.2013.05.023","article-title":"Neuroglial differentiation of adult enteric neuronal progenitor cells as a function of extracellular matrix composition","volume":"34","author":"Raghavan","year":"2013","journal-title":"Biomaterials"},{"key":"2021122704233629000_R13","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1089\/ten.tea.2013.0422","article-title":"Bioengineering of physiologically functional intrinsically innervated human internal anal sphincter constructs","volume":"20","author":"Gilmont","year":"2014","journal-title":"Tissue Eng Part A"},{"key":"2021122704233629000_R14","doi-asserted-by":"crossref","first-page":"e72948","DOI":"10.1371\/journal.pone.0072948","article-title":"The human gastrointestinal tract, a potential autologous neural stem cell source","volume":"8","author":"Hagl","year":"2013","journal-title":"PLoS One"},{"key":"2021122704233629000_R15","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1053\/j.gastro.2009.03.036","article-title":"Bioengineered internal anal sphincter derived from isolated human internal anal sphincter smooth muscle cells","volume":"137","author":"Somara","year":"2009","journal-title":"Gastroenterology"},{"key":"2021122704233629000_R16","doi-asserted-by":"crossref","first-page":"G188","DOI":"10.1152\/ajpgi.00335.2004","article-title":"Development of a three-dimensional physiological model of the internal anal sphincter bioengineered in vitro from isolated smooth muscle cells","volume":"289","author":"Hecker","year":"2005","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2021122704233629000_R17","first-page":"G869","article-title":"V. Genes, lineages, and tissue interactions in the development of the enteric nervous system","volume":"275","author":"Gershon","year":"1998","journal-title":"Am J Physiol"},{"issue":"suppl 1","key":"2021122704233629000_R18","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.1365-2982.2008.01094.x","article-title":"The enteric nervous system: Normal functions and enteric neuropathies","volume":"20","author":"Furness","year":"2008","journal-title":"Neurogastroenterol Motil"},{"key":"2021122704233629000_R19","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1002\/ar.21033","article-title":"Plasticity and neural stem cells in the enteric nervous system","volume":"292","author":"Sch\u00e4fer","year":"2009","journal-title":"Anat Rec (Hoboken)"},{"key":"2021122704233629000_R20","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1111\/j.1365-2982.2009.01428.x","article-title":"The microenvironment in chronic pancreatitis and pancreatic cancer induces neuronal plasticity","volume":"22","author":"Demir","year":"2010","journal-title":"Neurogastroenterol Motil"},{"key":"2021122704233629000_R21","doi-asserted-by":"crossref","first-page":"61.e7","DOI":"10.1111\/nmo.12015","article-title":"Nestin-expressing cells in the gut give rise to enteric neurons and glial cells","volume":"25","author":"Belkind-Gerson","year":"2013","journal-title":"Neurogastroenterol Motil"},{"key":"2021122704233629000_R22","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.brainres.2008.04.051","article-title":"Neural progenitors from isolated postnatal rat myenteric ganglia: Expansion as neurospheres and differentiation in vitro","volume":"1218","author":"Silva","year":"2008","journal-title":"Brain Res"},{"key":"2021122704233629000_R23","doi-asserted-by":"crossref","first-page":"e221","DOI":"10.1016\/j.jss.2011.01.016","article-title":"Transplantation of neonatal gut neural crest progenitors reconstructs ganglionic function in benzalkonium chloride-treated homogenic rat colon","volume":"167","author":"Pan","year":"2011","journal-title":"J Surg Res"},{"key":"2021122704233629000_R24","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1172\/JCI65963","article-title":"Transplanted progenitors generate functional enteric neurons in the postnatal colon","volume":"123","author":"Hotta","year":"2013","journal-title":"J Clin Invest"},{"key":"2021122704233629000_R25","doi-asserted-by":"crossref","first-page":"G741","DOI":"10.1152\/ajpgi.00225.2014","article-title":"Enteric neural progenitors are more efficient than brain-derived progenitors at generating neurons in the colon","volume":"307","author":"Findlay","year":"2014","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2021122704233629000_R26","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.surg.2013.12.023","article-title":"Perianal implantation of bioengineered human internal anal sphincter constructs intrinsically innervated with human neural progenitor cells","volume":"155","author":"Raghavan","year":"2014","journal-title":"Surgery"},{"key":"2021122704233629000_R27","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1007\/s00268-011-1088-5","article-title":"Short- and long-term results of open versus laparoscopic appendectomy","volume":"35","author":"Swank","year":"2011","journal-title":"World J Surg"},{"key":"2021122704233629000_R28","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1111\/j.1365-2982.2005.00687.x","article-title":"Glial cells in the gut","volume":"17","author":"R\u00fchl","year":"2005","journal-title":"Neurogastroenterol Motil"},{"key":"2021122704233629000_R29","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/glia.20445","article-title":"S100B expression defines a state in which GFAP-expressing cells lose their neural stem cell potential and acquire a more mature developmental stage","volume":"55","author":"Raponi","year":"2007","journal-title":"Glia"}],"container-title":["Stem Cells Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.5966%2Fsctm.2014-0238","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.5966%2Fsctm.2014-0238","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/4\/6\/548\/41864405\/stcltm_4_6_548.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/4\/6\/548\/41864405\/stcltm_4_6_548.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T02:49:08Z","timestamp":1642560548000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stcltm\/article\/4\/6\/548-554\/6397343"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,4,14]]},"references-count":29,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2015,4,14]]},"published-print":{"date-parts":[[2015,6,1]]}},"URL":"https:\/\/doi.org\/10.5966\/sctm.2014-0238","relation":{},"ISSN":["2157-6564","2157-6580"],"issn-type":[{"value":"2157-6564","type":"print"},{"value":"2157-6580","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,6,1]]},"published":{"date-parts":[[2015,4,14]]}}}