Network formation of enteric ganglion cells with Hirschsprung disease model

• Project/Area Number: 26462714
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatric surgery
• Research Institution: Keio University
• Principal Investigator: Shibata Shinsuke 慶應義塾大学, 医学部(信濃町), 講師 (70407089)
• Co-Investigator(Renkei-kenkyūsha): Fujimura Takumi 慶應義塾大学, 医学部, 助教 (80573443)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ヒルシュスプルング病 / 神経堤 / 幹細胞 / 腸管 / モデルマウス / 蛍光タンパク質 / 移植治療

Outline of Final Research Achievements

Hirschsprung disease is one of the major intestinal motility disorder, caused by the partial loss of intestinal ganglion cells derived from the absence or impaired migration of neural crest derived cells in early embryonic period. In this study, we established a new animal model for intestinal motility dysfunction by using the transgenic mouse strain, whose neural crest derived cells are labeled with green fluorescent protein. The analysis of the differentiation status of neural crest-derived cells and the functional abnormality of the gastrointestinal motility indicated that this model mouse continuously showed the similar phenotypes and pathophysiological courses of the human Hirschsprung disease patient. By creating a new disease model animal, it was possible to reveal a part of complicated mechanisms for the normal network formation and also a part of pathogenesis for intestinal motility disorder in vivo.

Research Products

• [Int'l Joint Research] Harvard University/University of California San Diego/University of Nebraska(米国)
• [Int'l Joint Research] University of Helsinki(Finland)
• [Int'l Joint Research] Harvard University(米国)
• [Journal Article] Enhanced Functional Recovery from Spinal Cord Injury in Aged Mice after Stem Cell Transplantation through HGF Induction (2017)
  • Author(s): Takano M, Kawabata S, Shibata S, Yasuda A, Nori S, Tsuji O, Nagoshi N, Iwanami A, Ebise H, Horiuchi K, Okano H, Nakamura M.
  • Journal Title: Stem Cell Reports Volume: 8(3) Issue: 3 Pages: 509-518
  • DOI: 10.1016/j.stemcr.2017.01.013
  • Peer Reviewed / Open Access
• [Journal Article] Skin-Derived Precursors as a Source of Progenitors for Corneal Endothelial Regeneration. (2017)
  • Author(s): Inagaki E, Hatou S, Higa K, Yoshida S, Shibata S, Okano H, Tsubota K, Shimmura S.
  • Journal Title: Stem Cells Transl Med Volume: 6(3) Issue: 3 Pages: 788-798
  • DOI: 10.1002/sctm.16-0162
  • Peer Reviewed / Open Access
• [Journal Article] Functional brain mapping using specific sensory-circuit stimulation and a theoretical graph network analysis in mice with neuropathic allodynia. (2016)
  • Author(s): Komaki Y, Hikishima K, Shibata S, Konomi T, Seki F, Yamada M, Miyasaka N, Fujiyoshi K, Okano HJ, Nakamura M, Okano H.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 37802-37802
  • DOI: 10.1038/srep37802
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] In utero exposure to valproic acid induces neocortical dysgenesis via dysregulation of neural progenitor cell proliferation/differentiation. (2016)
  • Author(s): Fujimura K, Mitsuhashi T, Shibata S, Shimozato S, Takahashi T.
  • Journal Title: Journal of Neuroscience Volume: 36 Issue: 42 Pages: 10908-10919
  • DOI: 10.1523/jneurosci.0229-16.2016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. (2016)
  • Author(s): Fox RG, Lytle NK, Jaquish DV, Park FD, Ito T, Bajaj J, Koechlein CS, Zimdahl B, Yano M, Kopp JL, Kritzik M, Sicklick JK, Sander M, Grandgenett PM, Hollingsworth MA, Shibata S, Pizzo D, Valasek MA, Sasik R, Scadeng M, Okano H, Kim Y, MacLeod AR, Lowy AM, Reya T.
  • Journal Title: Nature Volume: 534(7607) Issue: 7607 Pages: 407-411
  • DOI: 10.1038/nature17988
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7 (2016)
  • Author(s): Narumi S*, et al., Matsumoto N, et al.
  • Journal Title: Nat Genet Volume: 48 Issue: 7 Pages: 792-797
  • DOI: 10.1038/ng.3569
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LNGFR+THY-1+ Human Pluripotent Stem Cell-derived Neural Crest-Like Cells Have the Potential to Develop Into Mesenchymal Stem Cells (2016)
  • Author(s): Ouchi T, Morikawa S, Shibata S, Fukuda K, Okuno H, Fujimura T, Kuroda T, Ohyama M, Akamatsu W, Nakagawa T Okano H.
  • Journal Title: Differentiation Volume: 92(5) Issue: 5 Pages: 270-280
  • DOI: 10.1016/j.diff.2016.04.003
  • Peer Reviewed / Open Access
• [Journal Article] Sustained Effect of Hyaluronic Acid in Subcutaneous Administration to the Cochlear Spiral Ganglion. (2016)
  • Author(s): Inagaki Y, Fujioka M, Kanzaki S, Watanabe K, Oishi N, Itakura G, Yasuda A, Shibata S, Nakamura M, Okano HJ, Okano H, Ogawa K.
  • Journal Title: PLoS One in press Volume: 11 Issue: 4 Pages: e0153957-e0153957
  • DOI: 10.1371/journal.pone.0153957
  • Peer Reviewed / Open Access
• [Journal Article] Fluorescence Visualization of the Enteric Nervous Network in a Chemically Induced Aganglionosis Model (2016)
  • Author(s): Fujimura T*, Shibata S*, Shimojima N, Morikawa Y, Okano H, Kuroda T. (*equally contributed first author)
  • Journal Title: PLoS One Volume: 11(3):e0150579. Issue: 3 Pages: 1-14
  • DOI: 10.1371/journal.pone.0150579
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Applications of Mesenchymal Stem Cells and Neural Crest Cells in Craniofacial Skeletal Research. (2016)
  • Author(s): Morikawa S, Ouchi T, Shibata S, Fujimura T, Kawana H, Okano H, Nakagawa T.
  • Journal Title: Stem Cells International Volume: 2849879 Issue: 1 Pages: 1-8
  • DOI: 10.1155/2016/2849879
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Application of q-Space Diffusion MRI for the Visualization of White Matter (2016)
  • Author(s): Fujiyoshi K, Hikishima K, Nakahara J, Tsuji O, Hata J, Konomi T, Nagai T, Shibata S, Kaneko S, Iwanami A, Momoshima S, Takahashi S, Jinzaki M, Suzuki N, Toyama Y, Nakamura M, Okano H.
  • Journal Title: Journal of Neuroscience Volume: 36(9) Issue: 9 Pages: 2796-2808
  • DOI: 10.1523/jneurosci.1770-15.2016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Grafted human iPS cell-derived oligodendrocyte precursor cells contribute to robust remyelination of demyelinated axons after spinal cord injury (2016)
  • Author(s): Kawabata S, Takano M, Numasawa-Kuroiwa Y, Itakura G, Kobayashi Y, Nishiyama Y, Sugai K, Nishimura S, Iwai H, Isoda M, Shibata S, Kohyama J, Iwanami A, Toyama Y, Matsumoto M, Nakamura M, Okano H,
  • Journal Title: Stem Cell Reports Volume: 6(1) Issue: 1 Pages: 1-8
  • DOI: 10.1016/j.stemcr.2015.11.013
  • Peer Reviewed / Open Access
• [Journal Article] Novel in vivo imaging analysis of an inner ear drug delivery system: Drug availability in inner ear following different dose of systemic drug injections. (2015)
  • Author(s): Kanzaki S, Watanabe K, Fujioka M, Shibata S, Nakamura M, Okano HJ, Okano H, Ogawa K.
  • Journal Title: Hear Res. Volume: 330 Pages: 142-146
  • DOI: 10.1016/j.heares.2015.09.018
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Immuno-Electron Microscopy and Electron Microscopic In Situ Hybridization for Visualizing piRNA Biogenesis Bodies in Drosophila Ovaries. (2015)
  • Author(s): Shibata S*, Murota Y, Yoshimura M, Nagai T, Okano H, Siomi MC*. (*co-corresponding author)
  • Journal Title: Methods in Molecular Biology Volume: 1328 Pages: 163-178
  • DOI: 10.1007/978-1-4939-2851-4_12
  • ISBN: 9781493928507, 9781493928514
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Allogeneic neural stem/progenitor cells derived from embryonic stem cells promote functional recovery after transplantation into injured spinal cord of non-human primates (2015)
  • Author(s): Iwai H, Shimada H, Nishimura S, Kobayashi Y, Itakura G, Hori K, Hikishima K, Ebise H, Negishi N, Shibata S, Habu S, Toyama Y, Nakamura M, Okano H.
  • Journal Title: Stem Cells Translational Medicine Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Gene expression ontogeny of spermatogenesis in the marmoset uncovers primate characteristics during testicular development. (2015)
  • Author(s): Yu-Ching Lin Z, Hirano T, Shibata S, Seki NM, Kitajima R, Sedohara A, Siomi MC, Sasaki E, Siomi H, Imamura M, Okano H.
  • Journal Title: Dev Biol. Volume: - Issue: 1 Pages: 43-58
  • DOI: 10.1016/j.ydbio.2015.01.014
  • Peer Reviewed / Open Access
• [Journal Article] Connectomics: comprehensive approaches for whole-brain mapping. (2015)
  • Author(s): Shibata S, Komaki Y, Seki F, Inouye MO, Nagai T, Okano H.
  • Journal Title: Microscopy Volume: 64 Issue: 1 Pages: 57-67
  • DOI: 10.1093/jmicro/dfu103
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Migration and differentiation of transplanted enteric neural crest-derived cells in murine model of Hirschsprung's disease. (2015)
  • Author(s): Nishikawa R, Hotta R, Shimojima N, Shibata S, Nagoshi N, Nakamura M, Matsuzaki Y, Okano HJ, Kuroda T, Okano H, Morikawa Y.
  • Journal Title: Cytotechnology Volume: 印刷中
  • Peer Reviewed
• [Presentation] 霊長類ミクロ・マクロコネクトーム解析 (2016)
  • Author(s): Shibata S. Sasaki E.
  • Organizer: 生体ボリュームイメージング研究部会＆生理研研究会 合同ワークショップ「電子顕微鏡ビッグデータが拓くバイオメディカルサイエンス」
  • Place of Presentation: 岡崎コンファレンスセンター(愛知県岡崎市)
  • Year and Date: 2016-11-16
  • Invited
• [Presentation] ATUMtomeとMultiSEMを用いて世界最高速で広範囲を電子顕微鏡撮影 (2016)
  • Author(s): Shibata S.
  • Organizer: 第72回日本顕微鏡学会第72回学術講演会サテライト・ワークショップ
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-06-14
  • Invited
• [Presentation] 電子顕微鏡による大規模高速コネクトミクス解析 (2016)
  • Author(s): Shibata S, Okano H, Lichtman JW,
  • Organizer: 第121回日本解剖学会年会
  • Place of Presentation: ビックパレットふくしま(福島県郡山市)
  • Year and Date: 2016-03-27
  • Invited
• [Presentation] Application of the 3D-EM in Harvard and Keio University with ATUM (2015)
  • Author(s): Shibata S
  • Organizer: Array Tomography Workshop
  • Place of Presentation: Oxford (UK)
  • Year and Date: 2015-10-07
  • Int'l Joint Research / Invited
• [Presentation] Evaluation for the enteric ganglion cells with novel Hirschsprung's disease model (2015)
  • Author(s): Shibata S, Fujimura T, Kuroda T, Okano H.
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市)
  • Year and Date: 2015-07-28
• [Presentation] 電子顕微鏡を用いて蛋白質とRNAの局在を探る (2015)
  • Author(s): Shibata S
  • Organizer: 第140回 電子顕微鏡技術研究会
  • Place of Presentation: 東京大学医学部(東京都文京区)
  • Year and Date: 2015-06-06
  • Invited
• [Presentation] Approaches for brain connectomics (2015)
  • Author(s): Shibata S, Okano H, Lichtman JW,
  • Organizer: 日本顕微鏡学会 第71回学術講演会
  • Place of Presentation: 京都府京都市
  • Year and Date: 2015-05-13 – 2015-05-15
  • Invited
• [Presentation] Approaches for brain connectomics (2015)
  • Author(s): Shibata S, Okano H, Lichtman JW,
  • Organizer: 日本顕微鏡学会 第71回学術講演会
  • Place of Presentation: 国立京都国際会館(京都府京都市)
  • Year and Date: 2015-05-13
  • Invited
• [Presentation] 三次元電顕(電子顕微鏡)によるブレインマッピング技術革命 (2015)
  • Author(s): 芝田晋介, 岡野栄之, Jeff W Lichtman
  • Organizer: 日本顕微鏡学会「SEM連続断面観察による生物組織三次元再構築法研究部会」第三回研究会
  • Place of Presentation: 山梨県勝沼市
  • Year and Date: 2015-03-24 – 2015-03-25
  • Invited
• [Presentation] Evaluation of the Hirschsprung's disease model with the labeling for the neural crest derivatives (2014)
  • Author(s): Shibata S, Fujimura T, Kuroda T, Okano H.
  • Organizer: 第36回日本生物学的精神医学会・第57回日本神経化学会大会・合同年会
  • Place of Presentation: 奈良県奈良市
  • Year and Date: 2014-09-29 – 2014-10-01
• [Remarks] 慶應義塾大学医学部生理学教室ホームページ
  • URL: http://www.okano-lab.com/publication