非可逆性糖尿病性胃麻痺に対する神経幹細胞移植の開発

2013 Fiscal Year Annual Research Report

• Project/Area Number: 24659103
• Research Institution: Keio University
• Principal Investigator: 鈴木 秀和 慶應義塾大学, 医学部, 准教授 (70255454)
• Co-Investigator(Kenkyū-buntansha): 浦岡 俊夫 慶應義塾大学, 医学部, 講師 (80448216) ; 河瀬 聡 慶應義塾大学, 医学部, 特任助教 (80468496) ; 矢作 直久 慶應義塾大学, 医学部, 教授 (90292937)
• Keywords: 神経幹細胞 / 胃排出 / neurosphere / 13C酢酸呼気試験 / 糖尿病 / 脂質異常症

Research Abstract

消化管運動障害は有病率が高いが有効な治療法が確立しておらず、治療に難渋する疾患である。消化管運動障害のなかでも胃不全麻痺に対する治療として神経幹細胞移植に注目した。本研究では蛍光を発するVenus遺伝子に加え、化学発光を触媒するluciferaseが融合したffLuc transgenic mouseを用いた。ffLuc transgenic mouseの胎生胚から神経幹細胞含有皮質部或いは後根神経節を単離後、幹細胞の分化を抑制するためにEGF, FGFを加えフラスコ内浮遊培養でneurosphereを形成した。神経幹細胞をマウスの胃幽門部にガラス針装着シリンジで注入した。IVISで筋間神経叢にffLuc transgenic mouse由来細胞の生着が確認された。マウスの胃排出能測定は13C酢酸呼気試験を応用した。半消化態経腸栄養剤に混和した13C標識酢酸を絶食下に経口胃管で投与し各動物をチャンバー内に留置した。持続吸引下に呼気をバック内に回収しバック中の13C標識CO2は赤外分光分析で測定した。13Cの総投与量の半減期（T1/2）を胃排出能の指標とした。nNOSノックアウトマウスで神経幹細胞移植後の胃排出改善を確認した。対照(db/+m)に比しdb/dbマウスの一部でT1/2が延長せず約27%で胃排出が遅延した。筋間神経叢におけるnNOS発現は胃排出遅延を伴ったdb/dbマウスで顕著に低下した。胃排出遅延を伴ったdb/dbマウスでは胃筋間神経叢のnNOS発現が有意に低下した。脂質運搬に関与するアポリポプロテインE（apoE）のノックアウトマウスでも胃のnNOS発現が低下する。このapoEノックアウトマウスの胃排出能は遅延し、神経幹細胞移植により是正され筋間神経叢のnNOS発現も回復した。また、db/dbマウスの胃排出遅延群では、血清apoE値が有意に低下した。本研究により、神経幹細胞移植が疾患モデルで胃排出遅延を是正し、apoEが消化管運動障害のマーカーとなりうることが明らかになった。

Research Products

• [Journal Article] New pharmaceutical treatment of gastric MALT lymphoma: anti-angiogenesis treatment using VEGF receptor antibodies and celecoxib. (2014)
  • Author(s): Nakamura, M., Takahashi, T., Matsui, H., Takahashi, S., Murayama, SY., Suzuki, H., Tsuchimoto, K.
  • Journal Title: Curr. Pharm. Des. Volume: 20(7) Pages: 1097-1103
  • Peer Reviewed
• [Journal Article] Does bile reflux influence the progression of Barrett's esophagus to adenocarcinoma? (2014)
  • Author(s): Masaoka, T., Suzuki, H.
  • Journal Title: J. Neurogastroenterol. Motil. Volume: 20(1) Pages: 124-126
  • DOI: 10.5056/jnm.2014.20.1.124.
  • Peer Reviewed
• [Journal Article] A questionnaire-based survey on the diagnosis and management of inflammatory bowel disease in East Asian countries in 2012. (2014)
  • Author(s): Hida, N., Nakamura, S., Hahm, K-B., Sollano, J.D., Zhu, Q., Rani, A.A., Syam, A.F., Kachintorn, U., Ueno, F., Joh, T., Naito, Y., Suzuki, H., Takahashi, S., Fukudo, S., Fujiwara, Y., Kinoshita, Y., Uchiyama, K., Yamaguchi, Y., Yoshida, A., Arakawa, T., Matsumoto, T., The IGICS Study Group.
  • Journal Title: Digestion Volume: 89(1) Pages: 88-103
  • DOI: 10.1159/000356706.
  • Peer Reviewed
• [Journal Article] Greater loss of productivity among Japanese workers with gastroesophageal reflux disease (GERD) symptoms that persist vs resolve on medical therapy. (2014)
  • Author(s): Suzuki, H., Matsuzaki, J., Masaoka, T., Inadomi, J.M.
  • Journal Title: Neurogastroenterol. Motil. Volume: - Pages: -
  • DOI: 10.1111/nmo.12319.
  • Peer Reviewed
• [Journal Article] Superiority of pulmonary administration of mepenzolate bromide over other routes as treatment for chronic obstructive pulmonary disease. (2014)
  • Author(s): Tanaka, K., Kurotsu, S., Asano, T., Yamakawa, N., Kobayashi, D., Yamashita, Y., Yamazaki, H., Ishihara, T., Watanabe, H., Maruyama, T., Suzuki, H., Mizushima, T.
  • Journal Title: Sci. Rep. Volume: 4 Pages: 4510
  • DOI: 10.1038/srep04510.
  • Peer Reviewed
• [Journal Article] MicroRNAs in Barrett’s esophagus: Future prospects. (2014)
  • Author(s): Matsuzaki, J., Suzuki, H.
  • Journal Title: Front. Genet. Volume: 5 Pages: article 69
  • DOI: 10.3389/fgene.2014.00069.
  • Peer Reviewed
• [Journal Article] Effect of lansoprazole on the epigastric symptoms of functional dyspepsia (ELF study) : a multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial (2013)
  • Author(s): Suzuki, H., Kusunoki, H., Kamiya, T., Futagami, S., Yamaguchi, Y., Nishizawa, T., Iwasaki, E., Matsuzaki, J., Takahashi, S., Sakamoto, C., Haruma, K., Joh, T., Asakura, K., Hibi, T.
  • Journal Title: ueg journal Volume: 1(6) Pages: 445-452
  • DOI: 10.1177/2050640613510904
• [Journal Article] Validation of the GerdQ questionnaire for the management of gastroesophageal reflux disease in Japan (2013)
  • Author(s): Suzuki, H., Matsuzaki, J., Okada, S., Fukuhara, S., Hirata, K., Hibi, T.
  • Journal Title: ueg journal Volume: 1(3) Pages: 175-183
  • DOI: 10.1177/2050640613485238
• [Journal Article] Effect of ursodeoxycholic acid and endoscopic sphincterotomy in long-term stenting for common bile duct stones. (2013)
  • Author(s): Nishizawa, T., Suzuki, H., Takahashi, M., Kaneko, H., Suzuki, M., Hibi, T.
  • Journal Title: J. Gastroenterol. Hepatol. Volume: 28(1) Pages: 63-67
  • DOI: 10.1111/jgh.12012.
  • Peer Reviewed
• [Journal Article] Helicobacter pylori infection in functional dyspepsia. (2013)
  • Author(s): Suzuki, H., Moayyedi, P.
  • Journal Title: Nature Rev. Gastroenterol. Hepatol. Volume: 10(3) Pages: 168-174
  • DOI: 10.1038/nrgastro.2013.9.
  • Peer Reviewed
• [Journal Article] Improvement of reflux symptom related quality of life after Helicobacter pylori eradication therapy. (2013)
  • Author(s): Hirata, K., Suzuki, H., Matsuzaki, J., Masaoka, M., Saito, Y., Nishizawa, T., Iwasaki, E., Fukuhara, S., Okada, S., Hibi, T.
  • Journal Title: J. Clin. Biochem. Nutri. Volume: 52(2) Pages: 172-178
  • DOI: 10.3164/jcbn.12-107.
  • Peer Reviewed
• [Journal Article] Biliary findings assist in predicting enlargement of intraductal papillary mucinous neoplasms of the pancreas. (2013)
  • Author(s): Matsuzaki, J., Suzuki, H., Okuda, S., Tanimoto, A., Asakura, K., Fukuhara, S., Okada, S., Hirata, K., Mori, H., Masaoka, T., Higuchi, H., Hozawa, S., Kuribayashi, S., Takebayashi, T., Hibi, T.
  • Journal Title: Clin. Gastroenterol. Hepatol. Volume: 11(5) Pages: 548-554
  • DOI: 10.1016/j.cgh.2012.11.027.
  • Peer Reviewed
• [Journal Article] Musashi-1 post-transcriptionally enhances phosphotyrosine-binding domain- containing m-Numb protein expression in regenerating gastric mucosa. (2013)
  • Author(s): Takahashi, T., Suzuki, H., Imai, T, Shibata, S., Tabuchi, Y., Tsuchimoto, K., Okano, H., Hibi, T.
  • Journal Title: PLoS One Volume: 8(1) Pages: e53540
  • DOI: 10.1371/journal.pone.0053540.
  • Peer Reviewed
• [Journal Article] Impaired heme oxygenase-1 induction in the gastric antrum induces disruption of the interstitial cells of Cajal network in a rat model of streptozotocin-induced diabetes. (2013)
  • Author(s): Mogami, S., Suzuki, H., Tsugawa, H., Fukuhara, S., Hibi, T.
  • Journal Title: Neurogastroenterol. Motil. Volume: 25(7) Pages: 609-e465
  • DOI: 10.1111/nmo.12122.
  • Peer Reviewed
• [Journal Article] Progressive liver failure induced by everolimus for renal cell carcinoma in a 58-year-old male hepatitis B virus carrier. (2013)
  • Author(s): Mizuno, S., Yamagishi, Y., Ebinuma, H., Nakamoto, N., Katahira, M., Sasaki, A., Sakamoto, M., Suzuki, H., Kanai, T., Hibi, T.
  • Journal Title: Clin. J. Gastroenterol. Volume: 6(2) Pages: 188-192
  • Peer Reviewed
• [Journal Article] The role of microRNA in gastric malignancy. (2013)
  • Author(s): Nishizawa, T., Suzuki, H.
  • Journal Title: Int. J. Mol. Sci. Volume: 14(5) Pages: 9487-9496
  • DOI: 10.3390/ijms14059487.
  • Peer Reviewed
• [Journal Article] Delay of second-line eradication therapy for H. pylori can increase eradication failure. (2013)
  • Author(s): Nishizawa, T., Suzuki, H., Takahashi, M., Suzuki, M., Hibi, T.
  • Journal Title: J. Gastroenterol. Hepatol. Volume: 28(10) Pages: 1608-1610
  • DOI: 10.1111/jgh.12281.
  • Peer Reviewed
• [Journal Article] Trends of second-line eradication therapy for Helicobacter pylori in Japan: A Multicenter Study in the Tokyo Metropolitan Area. (2013)
  • Author(s): Asaoka, D., Nagahara, A., Matsuhisa, T., Takahashi, S., Tokunaga, K., Kawai, T., Suzuki, H., Suzuki, M., Nishizawa, T., Kurihara, N., Ito, M., Sasaki, H., Omata, F., Mizuno, S., Torii, A., Ohkusa, T., Mine, T., Sakaki, N.
  • Journal Title: Helicobacter Volume: 18(6) Pages: 468-472
  • DOI: 10.1111/hel.12063.
  • Peer Reviewed
• [Journal Article] CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence. (2013)
  • Author(s): Hirata, K., Suzuki, H., Imaeda, H., Matsuzaki, J., Tsugawa, H., Nagano, O., Asakura, K., Saya, H., Hibi, T.
  • Journal Title: Br. J. Cancer Volume: 109(2) Pages: 379-386
  • DOI: 10.1038/bjc.2013.314.
  • Peer Reviewed
• [Journal Article] Do we need to eradicate H. pylori in patients with GORD? (2013)
  • Author(s): Masaoka, T., Suzuki, H.
  • Journal Title: ueg journal Volume: 1(4) Pages: 223-225
  • DOI: 10.1177/2050640613497713
  • Peer Reviewed
• [Journal Article] Bile acids increase levels of microRNAs 221 and 222, leading to degradation of CDX2 during esophageal carcinogenesis. (2013)
  • Author(s): Matsuzaki, J., Suzuki, H., Tsugawa, H., Watanabe, M., Hossain, S., Arai, E., Saito, Y., Sekine, S., Akaike, T., Kanai, Y., Mukaisho, K.I., Auwerx, J., Hibi, T.
  • Journal Title: Gastroenterology Volume: 145(6) Pages: 1300-1311
  • DOI: 10.1053/j.gastro.2013.08.008.
  • Peer Reviewed
• [Journal Article] Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease. (2013)
  • Author(s): Tanaka, K., Ishihara, T., Sugizaki, T., Kobayashi D., Yamashita, Y., Tahara, K., Yamakawa, N., Iijima, K., Mogushi, K., Tanaka, H., Sato, K., Suzuki, H., Mizushima, T.
  • Journal Title: Nature Commun. Volume: 4 Pages: 2686
  • DOI: 10.1038/ncomms3686.
  • Peer Reviewed
• [Journal Article] Endoscopic microvascular patterns of gastrointestinal cancer. (2013)
  • Author(s): Nishizawa, T., Suzuki, H.
  • Journal Title: Microvasc. Rev. Commun. Volume: 6(1) Pages: 9-12
  • Peer Reviewed
• [Presentation] Bile Acids Enhance Oncogenic miR-221/222 in the Transformation From Barrett’s Esphagus to Adenocarcinoma. (2013)
  • Author(s): Matsuzaki, J., Suzuki, H., Tsugawa, H., Saito, Y., Hossain, S., Arai, E., Sekine, S., Kanai, Y., Watanabe, M., Akaike, T., Mukaisho, K., Auwerx, J., Hibi, Y.
  • Organizer: Digestive Disease Week 2013
  • Place of Presentation: Orlando
  • Year and Date: 20130519-20130523
• [Presentation] Expression of CD44 Variant 9 Contributes to 5-Fluorouracil Resistance in Gastric Cancer Trough Anti-Oxidative Stress Mechanism.
  • Author(s): Okada, S., Suzuki, H., Masaoka, T., Tsugawa, H., Matsuzaki, J., Fukuhara, S., Hirata, K., Mori, H., Saya, H., Hibi, T.
  • Organizer: Digestive Disease Week 2013
  • Place of Presentation: Orlando
• [Presentation] The Loss of Work Productivity Associated with Gastroesophageal Reflux Disease(GERD) in a Japanese Working Population.
  • Author(s): Suzuki, H., Matsuzaki, J., Masaoka, T., Okada, S., Inadomi, J., Hibi, T.
  • Organizer: Digestive Disease Week 2013
  • Place of Presentation: Orlando
• [Presentation] Application of 13C-acetic acid breath test for animals with impaired gastric motility.
  • Author(s): Fukuhara, S., Suzuki, H., Masaoka, T., Suemasu, S., Matsuzaki, J., Tsugawa, H., Okada, S., Hirata, K., Mori, H., Saito, Y., Mizushima, T., Hibi, T.
  • Organizer: Digestive Disease Week 2013
  • Place of Presentation: Orlando
• [Presentation] Role of microRNA and cancer stem cells in gastric carcinogenesis
  • Author(s): Hidekazu Suzuki
  • Organizer: The XXVIth International Workshop on Helicobacter and related bacteria in chronic digestive inflammation and gastric cancer
  • Place of Presentation: Madrid
  • Invited
• [Presentation] Analysis of CagA serotypes with Helicobacter pylori multiplex serology.
  • Author(s): Michel, A., Wang, S., Zhang, W., Kist, M., Figueroa, G., Dondog, B., Suzuki, H., Pawlita, M.
  • Organizer: The XXVIth International Workshop on Helicobacter and related bacteria in chronic digestive inflammation and gastric cancer
  • Place of Presentation: Madrid
• [Presentation] Trends of second-line eradication therapy for Helicobacter pylori in Japan: A Multicenter Study in the Tokyo Metropolitan Area.
  • Author(s): Asaoka, D., Nagahara, A., Matsuhisa, T., Takahashi, S., Tokunaga, K., Kawai, T., Kawakami, K., Suzuki, H., Suzuki, M., Nishizawa, T., Kurihara, N., Ito, M., Sasaki, H., Omata, F., Mizuno, S., Torii, A., Ohkusa, T., Mine, T., Sakaki, N.
  • Organizer: The XXVIth International Workshop on Helicobacter and related bacteria in chronic digestive inflammation and gastric cancer
  • Place of Presentation: Madrid
• [Presentation] Influence of Helicobacter pylori on gastric carcinogenesis and functional disturbance.
  • Author(s): Hidekazu Suzuki
  • Organizer: The International Joint Meeting of IBS Conference and Rome Committee in Tokyo
  • Place of Presentation: Tokyo
  • Invited
• [Presentation] Autophagy causing CagA degradation is triggered by cytoplasmic accumulation of low-density lipoprotein receptor-related protein-1 (LRP1) in gastric epithelial cells infected with H. pylori.
  • Author(s): Tsugawa, H., Matsuzaki, J., Okada, S., Fukuhara, S., Mori, H., Masaoka, T., Sato, A., Saya, H., Hatakayama, M., Hirayama, T., Suzuki, H.
  • Organizer: UEGW2013
  • Place of Presentation: Berlin
• [Presentation] H. pylori eradication for cancer prevention in clinical practice.
  • Author(s): Hidekazu Suzuki
  • Organizer: UEGW2013
  • Place of Presentation: Berlin
  • Invited
• [Presentation] Involvement of stemness factors in the intestinal transdifferentiation of gastric epithelial cells.
  • Author(s): Fujii, Y., Suzuki, H., Aburatani, H., Hatakayama, M.
  • Organizer: The 4th JCA-AACR Special Joint Conference
  • Place of Presentation: Urayasu
• [Presentation] CD44v9 play a role to anti-tumor effect against human gastric cancer by trastuzumab.
  • Author(s): Mori, H., Suzuki, H., Matsuzaki, J., Tsugawa, H., Fukuhara, S., Miyoshi, S., Masaoka, T., Kanai, T., Saya, H.
  • Organizer: The 4th JCA-AACR Special Joint Conference
  • Place of Presentation: Urayasu
• [Presentation] Escaped autophagy of H. pylori-derived oncoprotein CagA in gastric cancer stem-like cells.
  • Author(s): Hidekazu Suzuki
  • Organizer: The 4th JCA-AACR Special Joint Conference
  • Place of Presentation: Urayasu
  • Invited
• [Presentation] High-level resistance to metronidazole for Helicobacter pylori is more prevalent in patients with postprandial distress syndrome.
  • Author(s): Matsuzaki, J., Suzuki, H., Mori, H., Tsugawa, H., Masaoka, T., Miyoshi, S., Fukuhara, S., Kanai, T.
  • Organizer: The 4th Asian Pacific Single Topic Conference
  • Place of Presentation: Tagaytay
  • Invited
• [Presentation] Impairment of apolipoprotein E evokes delayed gastric emptying through nitrergic dysfunction.
  • Author(s): Fukuhara, S., Suzuki, H., Masaoka, T., Tsugawa, H., Okada, S., Mori, H., Hirata, K., Matsuzaki, J., Iwasaki, E., Mizushima, T., Suzuki, M.
  • Organizer: The 7th International Gastrointestinal Consensus Symposium (IGICS)
  • Place of Presentation: Fukushima
• [Presentation] Expression of CD44 variant 9 contributes to 5-fluorouracil resistance in gastric cancer through anti-oxidative stress mechanism.
  • Author(s): Miyoshi, S., Suzuki, H., Tsugawa, H., Masaoka, T., Matsuzaki, J., Fukuhara, S., Hirata, K., Mori, H., Kanani, T., Saya, H.
  • Organizer: 17th Biennial Meeting of Society for Free Radical Research International (SFRRI2014)
  • Place of Presentation: Kyoto
• [Presentation] The role of reactive oxygen species (ROS) in gastric carcinogenesis evoked by H. pylori infection.
  • Author(s): Tsugawa, H., Suzuki, H.
  • Organizer: 17th Biennial Meeting of Society for Free Radical Research International (SFRRI2014)
  • Place of Presentation: Kyoto
• [Presentation] Helicobacter pylori感染症 -酸化ストレス関連性病態機序-
  • Author(s): 鈴木秀和
  • Organizer: 第66回日本酸化ストレス学会学術集会
  • Place of Presentation: 名古屋
  • Invited
• [Presentation] 国民総除菌で胃がんを撲滅する
  • Author(s): 鈴木秀和
  • Organizer: 第19回日本ヘリコバクター学会学術集会
  • Place of Presentation: 長崎
  • Invited
• [Presentation] 過敏性腸症候群（IBS）における大腸鏡の現状と今後の貢献の可能性
  • Author(s): 水上健、小松弘一、鈴木秀和
  • Organizer: 第21回日本消化器病関連学会週間(JDDW2013)
  • Place of Presentation: 東京
• [Presentation] FD症状を緩和する緑茶主成分Epigallocatechin gallateによる小胞体シャペロンGRP78抑制を介したnNOS活性化機構の検討
  • Author(s): 正岡建洋、鈴木秀和、J.Tack
  • Organizer: 第21回日本消化器病関連学会週間(JDDW2013)
  • Place of Presentation: 東京
• [Presentation] H. pylori感染症とFD
  • Author(s): 鈴木秀和
  • Organizer: 第15回日本神経消化器病学会
  • Place of Presentation: 出雲
  • Invited
• [Presentation] 小胞体シャペロンGRP78はnNOS発現を制御する
  • Author(s): 正岡建洋、津川仁、福原誠一郎、三好佐和子、森英毅、Jan Tack, 金井隆典、鈴木秀和
  • Organizer: 第15回日本神経消化器病学会
  • Place of Presentation: 出雲
• [Presentation] 実験動物を用いたグレリン動態と胃排出障害
  • Author(s): 岩崎栄典、鈴木秀和、最上祥子、正岡建洋、金井隆典、塚田信廣
  • Organizer: 第50回記念日本臨床生理学会総会
  • Place of Presentation: 東京
• [Presentation] ピロリ菌感染症の診療を巡る最新知識
  • Author(s): 鈴木秀和
  • Organizer: 第42回日本総合健診医学会大会
  • Place of Presentation: 東京
  • Invited
• [Book] eBook: Helicobacter pylori - A Worldwide Perspective 2014 (2014)
  • Author(s): Suzuki, H., Nishizawa, T., Hibi, T.
  • Total Pages: -
  • Publisher: Bentham Science Publishers
• [Book] CANCER: OXIDATIVE STRESS AND DIETARY ANTIOXIDANTS (2014)
  • Author(s): Suzuki, H., Nishizawa, T.
  • Total Pages: pp33-40
  • Publisher: Academic Press