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Digestive Diseases and Sciences
Published in: Digestive Diseases and Sciences 12/2017

01-12-2017 | Original Article

Enteric Glial Dysfunction Evoked by Apolipoprotein E Deficiency Contributes to Delayed Gastric Emptying

Authors: Seiichiro Fukuhara, Tatsuhiro Masaoka, Soraya Nishimura, Masaya Nakamura, Juntaro Matsuzaki, Hitoshi Tsugawa, Sawako Miyoshi, Hideki Mori, Satoshi Kawase, Shinsuke Shibata, Hideyuki Okano, Takanori Kanai, Hidekazu Suzuki

Published in: Digestive Diseases and Sciences | Issue 12/2017

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Abstract

Background and Aim

Diabetes is the main cause of gastroparesis accompanying decreased neuronal nitric oxide synthase (nNOS) in myenteric ganglia of the stomach. Decreased nNOS expression in the stomach also results from defects in apolipoprotein E (ApoE), which is secreted by astrocytes and has neuroprotective effects on the central nervous system. However, the roles of ApoE and enteric glial cells on gastric motility are uncertain. In this study, ApoE and enteric glial cell alterations in gastroparesis were investigated.

Methods

Type 2 diabetic (db/db) mice and ApoE-knockout mice were analyzed. Gastric emptying was measured using the 13C acetic acid breath test. Expression levels of the pan-neuronal marker, protein gene product 9.5 (PGP 9.5), and glial marker, glial fibrillary acidic protein (GFAP) were examined by immunohistochemistry. Neural stem cells (NSCs) were injected into the gastric antral wall of ApoE-knockout mice.

Results

Delayed gastric emptying was observed in 27% of db/db mice with significant decreases in serum ApoE levels and GFAP expression in the gastric antrum. Gastric emptying was also delayed in ApoE-knockout mice, with a significant decrease in GFAP expression, but no change in PGP 9.5 expression. Transplantation of NSCs improved gastric emptying in ApoE-knockout mice through supplementation of GFAP-positive cells.

Conclusions

Our results suggest that decreased enteric glial cells in ApoE-knockout mice are crucial for development of delayed gastric emptying, and NSC transplantation is effective in restoring myenteric ganglia and gastric motility.
Literature
1.
Soykan I, Sivri B, Sarosiek I, Kiernan B, McCallum RW. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci. 1998;43:2398–2404.CrossRefPubMed
2.
3.
Guy RJ, Dawson JL, Garrett JR, et al. Diabetic gastroparesis from autonomic neuropathy: surgical considerations and changes in vagus nerve morphology. J Neurol Neurosurg Psychiatry. 1984;47:686–691.CrossRefPubMedPubMedCentral
4.
Takahashi T, Nakamura K, Itoh H, Sima AA, Owyang C. Impaired expression of nitric oxide synthase in the gastric myenteric plexus of spontaneously diabetic rats. Gastroenterology. 1997;113:1535–1544.CrossRefPubMed
5.
Tack J, Demedts I, Meulemans A, Schuurkes J, Janssens J. Role of nitric oxide in the gastric accommodation reflex and in meal induced satiety in humans. Gut. 2002;51:219–224.CrossRefPubMedPubMedCentral
6.
Vanormelingen C, Vanuytsel T, Masaoka T, et al. The normoglycaemic biobreeding rat: a spontaneous model for impaired gastric accommodation. Gut. 2016;65:73–81.CrossRefPubMed
7.
Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240:622–630.CrossRefPubMed
8.
DeMattos RB, Brendza RP, Heuser JE, et al. Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice. Neurochem Int. 2001;39:415–425.CrossRefPubMed
9.
Mauch DH, Nagler K, Schumacher S, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science. 2001;294:1354–1357.CrossRefPubMed
10.
Hayashi H, Campenot RB, Vance DE, Vance JE. Glial lipoproteins stimulate axon growth of central nervous system neurons in compartmented cultures. J Biol Chem. 2004;279:14009–14015.CrossRefPubMed
11.
Pitas RE, Ji ZS, Weisgraber KH, Mahley RW. Role of apolipoprotein E in modulating neurite outgrowth: potential effect of intracellular apolipoprotein E. Biochem Soc Trans. 1998;26:257–262.CrossRefPubMed
12.
Laskowitz DT, Sheng H, Bart RD, Joyner KA, Roses AD, Warner DS. Apolipoprotein E-deficient mice have increased susceptibility to focal cerebral ischemia. J Cereb Blood Flow Metab. 1997;17:753–758.CrossRefPubMed
13.
14.
Neunlist M, Rolli-Derkinderen M, Latorre R, et al. Enteric glial cells: recent developments and future directions. Gastroenterology. 2014;147:1230–1237.CrossRefPubMed
15.
16.
Bassotti G, Villanacci V, Cathomas G, et al. Enteric neuropathology of the terminal ileum in patients with intractable slow-transit constipation. Hum Pathol. 2006;37:1252–1258.CrossRefPubMed
17.
Panagamuwa B, Kumar D, Ortiz J, Keighley MR. Motor abnormalities in the terminal ileum of patients with chronic idiopathic constipation. Br J Surg. 1994;81:1685–1688.CrossRefPubMed
18.
Boyles JK, Pitas RE, Wilson E, Mahley RW, Taylor JM. Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Investig. 1985;76:1501–1513.CrossRefPubMedPubMedCentral
19.
Okano H, Temple S. Cell types to order: temporal specification of CNS stem cells. Curr Opin Neurobiol. 2009;19:112–119.CrossRefPubMed
20.
21.
Ogawa Y, Sawamoto K, Miyata T, et al. Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats. J Neurosci Res. 2002;69:925–933.CrossRefPubMed
22.
Iwanami A, Kaneko S, Nakamura M, et al. Transplantation of human neural stem cells for spinal cord injury in primates. J Neurosci Res. 2005;80:182–190.CrossRefPubMed
23.
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;129:1817–1824.CrossRefPubMed
24.
Uchida M, Endo N, Shimizu K. Simple and noninvasive breath test using 13C-acetic acid to evaluate gastric emptying in conscious rats and its validation by metoclopramide. J Pharmacol Sci. 2005;98:388–395.CrossRefPubMed
25.
Matsumoto K, Kimura H, Tashima K, Uchida M, Horie S. Validation of 13C-acetic acid breath test by measuring effects of loperamide, morphine, mosapride, and itopride on gastric emptying in mice. Biol Pharm Bull. 2008;31:1917–1922.CrossRefPubMed
26.
Hara-Miyauchi C, Tsuji O, Hanyu A, et al. Bioluminescent system for dynamic imaging of cell and animal behavior. Biochem Biophys Res Commun. 2012;419:188–193.CrossRefPubMed
27.
Kawase S, Imai T, Miyauchi-Hara C, et al. Identification of a novel intronic enhancer responsible for the transcriptional regulation of musashi1 in neural stem/progenitor cells. Mol Brain. 2011;4:14.CrossRefPubMedPubMedCentral
28.
Choi KM, Gibbons SJ, Nguyen TV, et al. Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis. Gastroenterology. 2008;135:2055–2064. (e2051–e2052).CrossRefPubMedPubMedCentral
29.
Ansquer JC, Foucher C, Aubonnet P, Le Malicot K. Fibrates and microvascular complications in diabetes–insight from the FIELD study. Curr Pharm Des. 2009;15:537–552.CrossRefPubMed
30.
Vincent AM, Hinder LM, Pop-Busui R, Feldman EL. Hyperlipidemia: a new therapeutic target for diabetic neuropathy. J Peripher Nerv Syst. 2009;14:257–267.CrossRefPubMedPubMedCentral
31.
Hinder LM, Vincent AM, Hayes JM, McLean LL, Feldman EL. Apolipoprotein E knockout as the basis for mouse models of dyslipidemia-induced neuropathy. Exp Neurol. 2013;239:102–110.CrossRefPubMed
32.
Snipes GJ, McGuire CB, Norden JJ, Freeman JA. Nerve injury stimulates the secretion of apolipoprotein E by nonneuronal cells. Proc Natl Acad Sci USA. 1986;83:1130–1134.CrossRefPubMedPubMedCentral
33.
Fullerton SM, Strittmatter WJ, Matthew WD. Peripheral sensory nerve defects in apolipoprotein E knockout mice. Exp Neurol. 1998;153:156–163.CrossRefPubMed
34.
Cabarrocas J, Savidge TC, Liblau RS. Role of enteric glial cells in inflammatory bowel disease. Glia. 2003;41:81–93.CrossRefPubMed
35.
Esposito G, Sarnelli G, Capoccia E, et al. Autologous transplantation of intestine-isolated glia cells improves neuropathology and restores cognitive deficits in beta amyloid-induced neurodegeneration. Sci Rep. 2016;6:22605.CrossRefPubMedPubMedCentral
36.
Pereira RV, Tronchini EA, Tashima CM, Alves EP, Lima MM, Zanoni JN. L-glutamine supplementation prevents myenteric neuron loss and has gliatrophic effects in the ileum of diabetic rats. Dig Dis Sci. 2011;56:3507–3516.CrossRefPubMed
37.
Liu W, Yue W, Wu R. Effects of diabetes on expression of glial fibrillary acidic protein and neurotrophins in rat colon. Auton Neurosci Basic Clin. 2010;154:79–83.CrossRef
38.
von Boyen GB, Steinkamp M, Reinshagen M, Schafer KH, Adler G, Kirsch J. Proinflammatory cytokines increase glial fibrillary acidic protein expression in enteric glia. Gut. 2004;53:222–228.CrossRef
39.
Qi R, Yang W, Chen J. Role of enteric glial cells in gastric motility in diabetic rats at different stages. J Huazhong Univ Sci Technol. 2013;33:496–500.CrossRef
40.
Iantorno G, Bassotti G, Kogan Z, et al. The enteric nervous system in chagasic and idiopathic megacolon. Am J Surg Pathol. 2007;31:460–468.CrossRefPubMed
41.
Vanuytsel T, Vanormelingen C, Vanheel H, et al. From intestinal permeability to dysmotility: the biobreeding rat as a model for functional gastrointestinal disorders. PLoS ONE. 2014;9:e111132.CrossRefPubMedPubMedCentral
42.
Baitsch D, Bock HH, Engel T, et al. Apolipoprotein E induces antiinflammatory phenotype in macrophages. Arterioscler Thromb Vasc Biol. 2011;31:1160–1168.CrossRefPubMedPubMedCentral
43.
Liu Y, Xu X, Dou H, Hua Y, Xu J, Hui X. Apolipoprotein E knockout induced inflammatory responses related to microglia in neonatal mice brain via astrocytes. Int J Clin Exp Med. 2015;8:737–743.PubMedPubMedCentral
44.
45.
Ohshiro K, Puri P. Reduced glial cell line-derived neurotrophic factor level in aganglionic bowel in Hirschsprung’s disease. J Pediatr Surg. 1998;33:904–908.CrossRefPubMed
46.
Rodrigues DM, Li AY, Nair DG, Blennerhassett MG. Glial cell line-derived neurotrophic factor is a key neurotrophin in the postnatal enteric nervous system. Neurogastroenterol Motil. 2011;23:e44–e56.CrossRefPubMed
47.
Laranjeira C, Sandgren K, Kessaris N, et al. Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury. J Clin Investig. 2011;121:3412–3424.CrossRefPubMedPubMedCentral
48.
49.
Brannvall K, Corell M, Forsberg-Nilsson K, Fex Svenningsen A. Environmental cues from CNS, PNS, and ENS cells regulate CNS progenitor differentiation. NeuroReport. 2008;19:1283–1289.CrossRefPubMed
50.
Kulkarni S, Zou B, Hanson J, et al. Gut-derived factors promote neurogenesis of CNS-neural stem cells and nudge their differentiation to an enteric-like neuronal phenotype. Am J Physiol Gastrointest Liver Physiol. 2011;301:G644–G655.CrossRefPubMedPubMedCentral
51.
Hotta R, Stamp LA, Foong JP, et al. Transplanted progenitors generate functional enteric neurons in the postnatal colon. J Clin Investig. 2013;123:1182–1191.CrossRefPubMedPubMedCentral
52.
Almond S, Lindley RM, Kenny SE, Connell MG, Edgar DH. Characterisation and transplantation of enteric nervous system progenitor cells. Gut. 2007;56:489–496.CrossRefPubMed
53.
Nori S, Okada Y, Yasuda A, et al. Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice. Proc Natl Acad Sci USA. 2011;108:16825–16830.CrossRefPubMedPubMedCentral
54.
Okano H, Nakamura M, Yoshida K, et al. Steps toward safe cell therapy using induced pluripotent stem cells. Circ Res. 2013;112:523–533.CrossRefPubMed
55.
Cheng LS, Hotta R, Graham HK, Nagy N, Goldstein AM, Belkind-Gerson J. Endoscopic delivery of enteric neural stem cells to treat Hirschsprung disease. Neurogastroenterol Motil. 2015;27:1509–1514.CrossRefPubMedPubMedCentral
Metadata
Title
Enteric Glial Dysfunction Evoked by Apolipoprotein E Deficiency Contributes to Delayed Gastric Emptying
Authors
Seiichiro Fukuhara
Tatsuhiro Masaoka
Soraya Nishimura
Masaya Nakamura
Juntaro Matsuzaki
Hitoshi Tsugawa
Sawako Miyoshi
Hideki Mori
Satoshi Kawase
Shinsuke Shibata
Hideyuki Okano
Takanori Kanai
Hidekazu Suzuki
Publication date
01-12-2017
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 12/2017
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-017-4820-7

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