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研究概要

概要

生物学教室では、変態期のアフリカツメガエルを用い、幹細胞制御の仕組みの解明に取り組んでいます。
両生類は卵からオタマジャクシへと発生し、さらに変態してカエルになることが知られています。変態期には、水中生活から陸上生活へと適応するために、前後肢の発達や尾の退縮など様々な形態的変化が起こります。小腸をはじめとする消化管では、変態期に幼生型固有の上皮がアポトーシスにより消失する一方、吸収上皮細胞の一部が成体幹細胞へと脱分化し、この幹細胞から哺乳類上皮に類似の成体型上皮が形成されます（図参照）。

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これまで

これまでに私たちは小腸の器官培養系を開発し、（1）幼生型から成体型への再構築は甲状腺ホルモンにより惹き起こされること、（2）幹細胞から成体型上皮が形成される過程では、周囲に形成される微小環境（ニッチ）との相互作用が不可欠であること、などを実験的に明らかにしてきました。幹細胞制御におけるニッチの重要性はヒトの小腸では古くから提唱され、ニッチの異常により癌などの疾患が起こると考えられていますが、その分子的実体は依然として謎に包まれています。そこで、幹細胞ニッチ形成の分子レベルでの解明を目指してツメガエルの小腸を実験モデルとして用い、甲状腺ホルモンに応答する遺伝子の発現や機能を培養やトランスジェニックの技術を駆使して解析しています。これまでに小腸再構築に関わるタンパク質として、次のようなものが見つかっています。
（１）マトリックスメタロプロテアーゼ（MMP）：MMPは一般に細胞外マトリックスを分解し、上皮のアポトーシスや癌の浸潤に関与すると言われています。小腸の再構築時に一過性に発現が上昇するMMP–11が、上皮のアポトーシスを促進することなどを培養下で証明しました。
（２）シグナル伝達に関わる分子：小腸の再構築時には、幹細胞で発現するソニックヘッジホッグ（Shh）が、近くの線維芽細胞に作用して骨形成タンパク質（BMP-4）を誘導し、さらにBMP-4が成体型上皮の分化を促進することを明らかにしました。この他、Wnt標準経路とNotch経路が幹細胞でその出現と同時に活性化されることを見出し、両経路の作用機構についても研究を進めています。これらのシグナル伝達経路は、ヒトの小腸でも幹細胞が存在する陰窩で活性化することが報告されており、幹細胞の制御に果たす役割が注目されます。その他、Hippo経路も幹細胞制御にかかわることを明らかにし、各経路がどのように作用し合うか調べています。
今後、さらに甲状腺ホルモン応答遺伝子の機能解析を進め、脊椎動物が進化の過程で保存してきた幹細胞制御の仕組みを明らかにしていくとともに、消化管の再生医学に有用な情報を提供していきたいと考えています。

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関連した研究業績

（2000年以降）

  1. Fujimoto K, Shibata Y, Hasebe T. (2023). Thyroid hormone-activated signaling pathways are essential for development of intestinal stem cells. J Nippon Med Sch 90(3):246-52. 

  2. Hasebe T, Fujimoto K, Ishizuya-Oka A. (2023). Stem cell development involves divergent thyroid hormone receptor subtype expression and epigenetic modifications in the amphibian intestine during metamorphosis. Vitam Horm 122:1-22

  3. Hasebe T, Fujimoto K, Ishizuya-Oka A. (2022) Essential roles of YAP-TEAD complex in adult stem cell development during thyroid hormone-induced intestinal remodeling of Xenopus laevis. Cell Tissue Res 388(2): 313-329.

  4. Hasebe T, Fujimoto K, Ishizuya-Oka A. (2020) Thyroid hormone-induced expression of Foxl1 in subepithelial fibroblasts correlates with adult stem cell development during Xenopus intestinal remodeling. Sci Rep 10: 20715

  5. Hasebe T, Fujimoto K, Buchholz DR, Ishizuya-Oka A. (2020) Stem cell development involves divergent thyroid hormone receptor subtype expression and epigenetic modifications in the Xenopus metamorphosing intestine. Gen Comp Endocrinol 292: 113441

  6. Fujimoto K, Hasebe T, Kajita M, Ishizuya-Oka A. (2018) Expression of hyaluronan synthases upregulated by thyroid hormone is involved in intestinal stem cell development during Xenopus laevis metamorphosis. Dev Genes Evol 228:267-273

  7. Hasebe T, Fujimoto K, Kajita M, Ishizuya-Oka A. (2017) Essential roles of thyroid hormone-regulated hyaluronan/CD44 signaling in adult stem cell development during Xenopus laevis intestinal remodeling. Stem Cells 35: 2175-2183

  8. Hasebe T, Fujimoto K, Kajita M, Fu L, Shi Y-B, Ishizuya-Oka A. (2017) Thyroid hormone-induced activation of Notch signaling is required for adult intestinal stem cell development during Xenopus laevis metamorphosis. Stem Cells 35:1028-1039

  9. Hasebe T, Fujimoto K, Kajita M, Ishizuya-Oka A. (2016) Thyroid hormone activates Wnt/beta-catenin signaling involved in adult epithelial development during intestinal remodeling in Xenopus laevis. Cell Tissue Res. 365:309-318

  10. Wen L, Hasebe T, Miller TC, Ishizuya-Oka A, Shi Y-B. (2015) A requirement for hedgehog signaling in thyroid hormone-induced postembryonic intestinal remodeling. Cell Biosci. 5: 13

  11. Ishizuya-Oka A, Kajita M, Hasebe T. (2014). Thyroid hormone-regulated Wnt5a/Ror2 signaling is essential for dedifferentiation of larval epithelial cells into adult stem cells in the Xenopus laevis intestine. PLoS ONE 9(9):e107611.

  12. Sun G, Heimeier RA, Fu L, Hasebe T, Das B, Ishizuya-Oka A, Shi Y-B. (2013). Expression profiling of intestinal tissues implicates tissue-specific genes and pathways essential for thyroid hormone-induced adult stem cell development. Endocrinology 154:4396-4407.

  13. Hasebe T, Fu L, Miller TC, Zhang Y,Shi Y-B, Ishizuya-Oka A. (2013). Thyroid hormone-induced cell-cell interactions are required for the development of adult intestinal stem cells. Cell Biosci. 3: 18.

  14. Miller TC, Sun G, Hasebe T, Fu L, Heimeier RA, Das B, Ishizuya-Oka A, Shi Y-B. (2013). Tissue-specific upregulation of MDS/EVI gene transcripts in the intestine by thyroid hormone during Xenopus metamorphosis. PLoS One 8: e55585.

  15. Ishizuya-Oka A, Hasebe T. (2013). Establishment of intestinal stem cell niche during amphibian metamorphosis. Curr. Top. Dev. Biol. 103: 305-327.

  16. Hasebe T, Kajita M, Fu L, Shi Y-B, Ishizuya-Oka A. (2012). Thyroid hormone-induced sonic hedgehog signal up-regulates its own pathway in a paracrine manner in the Xenopus laevis intestine during metamorphosis. Dev. Dyn. 241, 403-414.

  17. Hasebe T, Buchholz DR, Shi YB, Ishizuya-Oka A. (2011). Epithelial-connective tissue interactions induced by thyroid hormone receptor are essential for adult stem cell development in the Xenopus laevis intestine. Stem Cells 29: 154-161.

  18. Ishizuya-Oka A, Hasebe T, Buchholz DR, Kajita M, Fu L, Shi Y-B. (2009) The origin of the adult intestinal stem cells induced by thyroid hormone in Xenopus laevis. FASEB J. 23: 2568-2575.

  19. Hasebe T, Kajita M, Shi Y-B, Ishizuya-Oka A. (2008) Thyroid hormone-upregulated hedgehog interacting protein is involved in larval-to-adult intestinal remodeling by regulating sonic hedgehog signaling pathway in Xenopus laevis. Dev. Dyn. 237: 3006-3015

  20. Ishizuya-Oka A, Hasebe T. (2008) Sonic hedgehog and bone morphogenetic protein-4 signaling pathway involved in epithelial cell renewal along the radial axis of the intestine.  Digestion 77(suppl.1): 42-47

  21. Ishizuya-Oka A, Shi Y-B. (2008) Thyroid-hormone regulation of stem cell development during intestinal remodeling.  Mol. Cell. Endocrinol. 288:71-78

  22. Fu L, Hasebe T, Ishizuya-Oka A, Shi Y-B. (2007) Roles of matrix metalloproteinases and ECM remodeling during thyroid hormone-dependent intestinal metamorphosis in Xenopus laevis. Organogenesis 3: 14-19 

  23. Ishizuya-Oka A. (2007) Regeneration of the amphibian intestinal epithelium under the control of stem cell niche. Dev. Growth Differ. :49:99-107.

  24. Ishizuya-Oka A, Shi Y-B. (2007) Regulation of adult intestinal epithelial Stem cell development by thyroid hormone during Xenopus laevis metamorphosis.  Dev. Dyn. 236: 3358-3368

  25. Shi Y-B, Fu L, Hasebe T, Ishizuya-Oka A. (2007). Regulation of ECM remodeling and cell fate determination by matrix metalloproteinase strmoelysin-3 during thyroid hormone-dependent postembryonic development.  Pharmacol. & Ther. 116: 391-400

  26. Hasebe T, Kajita M, Fujimoto K, Yaoita Y, Ishizuya-Oka A. (2007) Expression profiles of the duplicated matrix metalloproteinase-9 genes suggest their different roles in apoptosis of larval intestinal epithelial cells during Xenopus laevis metamorphosis. Dev. Dyn. 236: 2338-2345

  27. Ishizuya-Oka A, Hasebe T, Shimizu K, Suzuki K, Ueda S. (2006) Shh/BMP-4 signaling pathway is essential for intestinal epithelial development during Xenopus larval-to-adult remodeling. Dev. Dyn. 235: 3240-3249

  28. Ishizuya-Oka A, Shi Y-B. (2005) Molecular mechanisms for thyroid hormone-induced remodeling in the amphibian digestive tract: a model for studying organ regeneration.  Dev. Growth Differ. 47:601-607

  29. Ikuzawa M, Shimizu K, Yasumasu S, Iuchi I, Shi Y-B, Ishizuya-Oka A. (2005) Thyroid hormone-induced expression of a bZip-containing transcription factor activates epithelial cell proliferation during Xenopus larval-to-adult intestinal remodeling.  Dev. Genes Evol. 216:109-118

  30. Fu L, Ishizuya-Oka A, Buchholz DR, Amano T, Shi Y-B. (2005) A causative role of stromelysin-3 in ECM remodeling and epithelial apoptosis during intestinal metamorphosis in Xenopus laevis.  J. Biol. Chem. 280: 27856-27865

  31. Buchholz DR, Ishizuya-Oka A, Shi Y-B. (2004) Spatial and temporal expression pattern of a novel gene in the frog Xenopus laevis: correlations with adult intestinal epithelial differentiation during metamorphosis. Gene Express. Patt. 4: 321-328

  32. Ishizuya-Oka A, Shimizu K, Sakakibara S, Okano H, Ueda S. (2003) Thyroid hormone-up-regulated expression of Musashi-1 is specific for progenitor cells of the adult epithelium during amphibian gastrointestinal remodeling.  J. Cell Sci. 116: 3157-3164

  33. Shimizu K, Ishizuya-Oka A, Amano T, Yoshizato K, Ueda S. (2002) Isolation of connective tissue-specific genes involved in Xenopus intestinal remodeling: thyroid hormone up-regulates Tolloid/BMP-1 expression. Dev. Gene Evol. 212: 357-364

  34. Ishizuya-Oka A, Ueda S, Amano T, Shimizu K, Suzuki K, Ueno N, Yoshizato K. (2001) Thyroid hormone-dependent and fibroblast-specific expression of BMP-4 correlates with adult epithelial development during amphibian intestinal remodeling.  Cell Tissue Res. 303: 187-195

  35. Ishizuya-Oka A, Ueda S, Inokuchi T, Amano T, Damjanovski S, Stolow M, Shi Y-B. (2001) Thyroid hormone-induced expression of Sonic hedgehog correlates with adult epithelial development during remodeling of the Xenopus stomach and intestine.  Differentiation 69: 27-37

  36. Shi Y-B, Ishizuya-Oka A. (2001) Thyroid hormone regulation of apoptotic tissue remodeling: Implications from molecular analysis of amphibian metamorphosis.  Prog. Nucleic Acid Res. Mol. Biol. 65: 53-100

  37. Damjanovski S, Puzianowska-Kuznicka M, Ishizuya-Oka A, Shi Y-B. (2000) Differential regulation of three thyroid hormone-responsive matrix metalloproteinase genes implicates distinct functions during frog embryogenesis. FASEB J. 14: 503-510

  38. Ishizuya-Oka A, Li Q, Amano T, Damjanovski S, Ueda S, Shi Y-B. (2000) Requirement for matrix metalloproteinase stromelysin-3 in cell migration and apoptosis during tissue remodeling.  J. Cell Biol.150: 1177-1188

  39. Ishizuya-Oka A, Ueda S. (2000) Molecular aspects of epithelial-connective tissue interactions during the intestinal remodeling.  Acta Histochem. Cytochem. 33: 177-184

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