間葉系幹細胞の分離と幹細胞可塑性を利用した臓器再構築

• Project/Area Number: 14081208
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: 梅澤 明弘 国立成育医療センター(研究所), 生殖医療研究部, 部長 (70213486)
• Project Period (FY): 2002 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥54,000,000 (Direct Cost: ¥54,000,000); Fiscal Year 2006: ¥10,900,000 (Direct Cost: ¥10,900,000); Fiscal Year 2005: ¥9,400,000 (Direct Cost: ¥9,400,000); Fiscal Year 2004: ¥11,700,000 (Direct Cost: ¥11,700,000); Fiscal Year 2003: ¥11,000,000 (Direct Cost: ¥11,000,000); Fiscal Year 2002: ¥11,000,000 (Direct Cost: ¥11,000,000)
• Keywords: 骨髄 / 間質細胞 / 間葉系幹細胞 / 再生医学 / 細胞移植 / 寿命延長

Research Abstract

間葉系幹細胞の可塑性を利用した臓器再構築への試みとして、胎盤、小児多指症、小児眼科手術検体由来組織の培養を行った。これらの組織は従来までの間葉系細胞と同様の培養条件で分離可能であり、増殖する細胞が存在することを明らかにした。しかしながらこれらヒト組織由来の細胞群は、旺盛な増殖能力を有しているものの、組織を細かく分離した後に培養を開始すると増殖が悪くなることから、細胞培養条件の詳細な検討を行った。
ヒト間葉系幹細胞は一定回数分裂した後増殖を停止する。ヒト間葉系細胞に未分化幹細胞性を維持した状態で細胞寿命を延長する技術を開発することは極めて重要な意義を有する。我々は前年度までに、遺伝子導入による細胞の寿命延長の機構を明らかにしてきた。ヒト間葉系幹細胞はテロメア短縮による絶対寿命が存在し、細胞老化の過程でRb経路を活性化するp16Ink4aの発現増加が見られ、p16の発現上昇によるRb経路の活性化が細胞寿命を規定していた。また、ヒト間葉系細胞の寿命延長にはテロメラーゼ活性の誘導の他にRb/p16経路の活性化阻止が必要であることを明確にした。将来、臨床応用をめざす上でp16Ink4aの発現増加機構を解明し、遺伝子導入によらないp16Ink4aの発現幹細胞性を保持したまま、寿命を延長させる技術は開発可能である。また、マイクロアレイの結果より、組織特異的な遺伝子発現パターンを検討した。

Research Products

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• [Journal Article] Histopathological and Behavioral Improvement of Murine Mucopolysaccharidosis Type VII by Intracerebral Transplantation of Neural Stem Cells. (2006)
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• [Journal Article] Combination of hTERT and bmi-1, E6, or E7 induces prolongation of the life span of bone marrow stromal cells from an elderly donor without affecting their neurogenic potential. (2005)
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• [Journal Article] Membranous osteogenesis system modeled with KUSA-A1 mature osteoblasts. (2005)
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• [Journal Article] Molecular and cell biological properties of mouse osteogenic mesenchymal progenitor cells, Kusa. (2005)
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• [Journal Article] Combination of hTERT and Bmi-1, E6 or E7 induce prolongation of the life span of bone marrow stromal cells from an elderly donor without affecting their neurogenic potential. (2005)
  • Author(s): Mori, T., Kiyono, et al.
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• [Journal Article] Immortalization of human fetal cells: The life span of umbilical-cord-blood-derived cells can be prolonged without manipulating p16INK4a/RB braking pathway. (2005)
  • Author(s): Terai, M., Uyama, T., Sugiki, T., Li, X-K., Umezawa, A., Kiyono, T
  • Journal Title: Mol.Biol.Cell 16(3) Pages: 1491-1499
• [Publications] Imabayashi, H: "Redifferentiation of dedifferentiated chondrocytes and chondrogenesis of human bone marrow stromal cells via chondrosphere formation with expression profiling by large-scale cDNA analysis."Experimental Cell Research. 288. 35-50 (2003)
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• [Publications] Yabe, H.: "Matrix Metalloproteinase (MMP)-1 and -3 expression in Ewing's sarcoma may be due to loss of accessibility of the MMP regulatory element to the specific fusion protein in vivo"Biochem. Biophys. Res. Commun.. 293. 61-71 (2002)
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• [Publications] Fukuma, M.: "Up-regulation of Id2,an oncogenic helix-loop-helix protein, is mediated by the chimeric EWS/ets protein in Ewing sarcoma"Oncogene. 22. 1-9 (2003)
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• [Publications] 五條 理志: "多能性体性幹細胞としての間葉系幹細胞"最新医学. 57・1. 38-46 (2002)
• [Publications] 五條 理志: "間葉系幹細胞の分化制御機構"炎症と免疫. 10・1. 13-18 (2002)
• [Publications] 梅澤 明弘: "間葉系幹細胞による臓器再生"化学と生物. 40・6. 362-369 (2002)
• [Publications] 梅澤 明弘: "間葉系幹細胞(mesenchymaal stem cell)による造血再生"血液・腫瘍科. 44・2. 126-136 (2002)
• [Publications] 梅澤 明弘: "間葉系幹細胞"医学のあゆみ. 200・13. 1127-1228 (2002)
• [Publications] 梅澤 明弘: "間葉系幹細胞"ゲノム医学. 2・1. 87-94 (2002)
• [Publications] 梅澤 明弘: "間葉系幹細胞をもちいた再生医療研究"分子細胞治療. 1・1. 31-37 (2002)
• [Publications] 梅澤 明弘: "幹細胞とエピジェネティクス"Molecular Medicine 別刷. 39・7. 816-822 (2002)
• [Publications] 梅澤 明弘: "再生医療"小児科臨床. 55・5. 844-846 (2002)
• [Publications] 梅沢 明弘: "間葉系幹細胞"再生医学再生医療 現代化学増刊. 41. 16-23 (2002)
• [Publications] 梅澤 明弘: "骨芽細胞から神経への転換"最新医学 別刷. 57・7. 1640-1647 (2002)
• [Publications] 竹田 征治: "筋ジストロフィーに対する再生治療"医学のあゆみ. 204・3. 179-182 (2003)
• [Publications] 梅澤 明弘: "組織幹細胞と生殖細胞の再生医学"ドクターズマガジン. 8・33. 40-41 (2003)
• [Publications] 森 泰昌: "再生医学と幹細胞-成体幹細胞"日医雑誌. 129・3. 307-312 (2003)
• [Publications] 井出 利憲: "老化研究が分かる"羊土社. 124 (2002)
• [Publications] 堀内 正嗣: "生活習慣と遺伝子疾患"メディカルレビュー社. 396 (2002)