DNA damage response in human hematopoietic stem cell

• Project/Area Number: 22790299
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: Tokai University
• Principal Investigator: YAHATA Takashi 東海大学, 医学部, 講師 (10398753)
• Co-Investigator(Renkei-kenkyūsha): ANDO Kiyoshi 東海大学, 医学部, 教授 (70176014)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 再生医学 / 造血幹細胞 / 移植 / 酸化ストレス / DNA障害 / 再生医療 / ヒト化モデル動物 / DNA損傷 / 自己複製 / 幹細胞移植 / ヒト化モデルマウス

Research Abstract

Stem cells of highly regenerative organs including blood are susceptible to endogenous DNA damage caused by both intrinsic and extrinsic stress. In this study, we demonstrate that the serial transplantation of human HSCs into immunodeficient mice triggers replication stress that induces incremental elevation of intracellular reactive oxygen species(ROS) levels and the accumulation of persistent DNA damage within the human HSCs. The study reveals that ROS play a causative role for DNA damage and the regulation of ROS have a major influence on human HSC aging.

Research Products

• [Journal Article] Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells (2011)
  • Author(s): Yahata T, Takanashi T, Muguruma Y, Ibrahim AA, Matsuzawa H, Uno T, Sheng Y, Onizuka M, Ito M, Kato S, Ando K
  • Journal Title: Blood Volume: 118(11) Pages: 2941-50
  • NAID: 40019489714
  • Peer Reviewed
• [Journal Article] MDS stem cells suppress normal hematopoiesis by niche invasion and microenvironment disruption (2011)
  • Author(s): Muguruma Y, Matsushita H, Yahata T, Yumino S, Tanaka Y, Miyachi H, Ogawa Y, Kawada H, Ito M, Ando K
  • Journal Title: Haematologica Volume: 96(4) Pages: 543-51
  • Peer Reviewed
• [Journal Article] Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells (2011)
  • Author(s): Yahata, T.
  • Journal Title: Blood Volume: 118 Issue: 11 Pages: 2941-2950
  • DOI: 10.1182/blood-2011-01-330050
  • NAID: 40019489714
  • Peer Reviewed
• [Journal Article] Establishment of xenograft model of human myelodysplastic syndromes (2011)
  • Author(s): Muguruma Y, Matsushita H, Yahata H, Yumino S, Tanaka Y, Miyachi H, Ogawa Y, Kawada H, Ito M, Ando K
  • Journal Title: Haematologica Volume: 96 Issue: 4 Pages: 543-551
  • DOI: 10.3324/haematol.2010.027557
  • Peer Reviewed
• [Journal Article] Adipocyte-derived mesenchymal stem cells facilitate hematopoiesis in vitro and in vivo : advantages over bone marrow-derived mesenchymal stem cells (2010)
  • Author(s): Nakao N, Nakayama T, Yahata T, Muguruma Y, Miyata Y, Naoe T
  • Journal Title: Am J Pathol Volume: 117(2) Pages: 547-54
  • Peer Reviewed
• [Journal Article] Establishment of xenograft model of human myelodysplastic syndromes. (2010)
  • Author(s): Muguruma., et al
  • Journal Title: Hematologica Volume: (In press)
  • Peer Reviewed
• [Journal Article] Adipose tissue-derived mesenchymal stem cells facilitate hematopoiesis in vitro and in vivo : advantages over bone marrow-derived mesenchymal stem cells. (2010)
  • Author(s): Nakao N., et al.
  • Journal Title: Am J Pathol. Volume: 177巻2号 Pages: 547-545
  • Peer Reviewed
• [Journal Article] 造血幹細胞ニッチ (2010)
  • Author(s): 八幡崇
  • Journal Title: Medical Science Digest Volume: 36巻6号 Pages: 2-4
• [Presentation] Klothoマウス敗血症モデルにおける免疫機能解析/Immune analysis of septic Klotho mice (2011)
  • Author(s): Inoue S., et al.
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ
  • Year and Date: 2011-11-27
• [Presentation] APL mice model using PML-RARA-transduced CD34-positive hematopoietic cells from human cord blood (2011)
  • Author(s): Hiromichi Matsushita, Takashi Yahata, Yoshihiko Nakamura, Yin Sheng, Yukari Muguruma, Hideyuki Matsuzawa Tomoko Uno, Tomomi Takanashi, Tadayuki Sato, Masayuki Tanaka, Hideki Hayashi, Makoto Onizuka, Yoshiaki Ogawa, Hayato Miyachi, Kiyoshi Ando
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋(名古屋国際会議場)
  • Year and Date: 2011-10-16
• [Presentation] CD34+/CD38+ cells from human cord blood initiate APL by induction of PML-RARA (2011)
  • Author(s): Matsushita H., et al.
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2011-10-16
• [Presentation] Activation of Fibrinolytic Pathway Using a Novel Small Molecule Enhaneed Hematopoietic Regeneration (2011)
  • Author(s): Ibrahim Abd Aziz, et al.
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2011-10-15
• [Presentation] Activation of Fibrinolytic Pathway Using a Novel Small Molecule Enhanced Hematopoietic Regeneration (2011)
  • Author(s): Abd Aziz Ibrahim, Takashi Yahata, Tomomi Takanashi, Toshio Miyata, and Kiyoshi Ando
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋(名古屋国際会議場)
  • Year and Date: 2011-10-14
• [Presentation] Notch signals regulate hematopoietic homeostasis through osteoblastic niche maintenance (2010)
  • Author(s): Yukari Muguruma, Takashi Yahata, Shizu Yumino, Yin Sheng, Katsuto Hozumi, Kiyoshi Ando
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 神奈川(パシフィコ横浜)
  • Year and Date: 2010-09-24
• [Presentation] Accumulation of DNA-damage limits the self-renewal capacity of human hematopoietic stem cells (2010)
  • Author(s): Takashi Yahata, Tomomi Takanashi, Hideyuki Matsuzawa, Yin Sheng, Tomoko Uno, Makoto Onizuka, Shunichi Kato, Kiyoshi Ando
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 神奈川(パシフィコ横浜)
  • Year and Date: 2010-09-24
• [Presentation] DNA損傷の蓄積はヒト造血幹細胞の自己複製能を制限する (2010)
  • Author(s): 八幡崇
  • Organizer: 日本血液学会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-24
• [Presentation] Notch signals regulate hematopoietic homeostasis through osteoblastic niche maintenance (2010)
  • Author(s): 六車ゆかり
  • Organizer: 日本血液学会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-09-24
• [Presentation] 骨芽細胞におけるDelta-like ligand1の発現が骨代謝維持に重要である (2010)
  • Author(s): 六車ゆかり
  • Organizer: 日本骨代謝学会
  • Place of Presentation: 京王プラザホテル(東京都)
  • Year and Date: 2010-07-23
• [Presentation] DNA損傷の蓄積がヒト造血幹細胞の再生能力を低下させる (2010)
  • Author(s): 八幡崇
  • Organizer: 日本サイトメトリー学会
  • Place of Presentation: 東京慈恵医科大学(東京都)
  • Year and Date: 2010-06-26