The role of transcription factor KLF2 in the regulation of hematopoiesis

• Project/Area Number: 17K16201
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Ishibashi Tomohiko 国立研究開発法人国立循環器病研究センター, 研究所, 上級研究員 (30722285)
• Research Collaborator: Tokudome Takeshi
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: KLF2 / 血管内皮細胞 / Klf2 / 血液内科学 / 造血幹細胞

Outline of Final Research Achievements

Vasculature in the bone marrow (BM) microenvironment plays a significant role in the regulation of hematopoiesis. Kruppel-like factor-2 (Klf2) is a transcription factor, which plays an important role in the regulation of endothelial cell function. To elucidate the interaction between vascular stability and hematopoiesis, we analyzed Tie2-Klf2-transgenic (Tg) mice, which express Klf2 under the regulation of Tie2 promoter. We confirmed that BM LSK cells and CD31-positive endothelial cells from Tie2-Klf2-Tg mice expressed the higher levels of Klf2 than those from wild-type control mice. Tie2-Klf2-Tg mice showed increased B-lineage progenitors after the Pro-B stage in the BM. We also analyzed mice which overexpress Angiopoietin-1, which is a ligand for the Tie2 receptor and has a vascular stabilizing effect, and these mice also showed increased number of lymphoid progenitors. These results suggest the close interaction between vascular stability and hematopoiesis.

Academic Significance and Societal Importance of the Research Achievements

造血幹細胞は加齢にしたがって質的に変化し、リンパ球産生能が低下するなどの老化現象が生じることが知られている。一方、骨髄の血管構造も加齢とともに変化することが報告されている。本研究の成果は、血管安定性を制御することでリンパ球系への分化能を回復できる可能性を示唆しており、加齢に伴って低下したリンパ球分化能を回復するなどの臨床応用へ向けた基盤となると考えられる。また、研究代表者は以前に白血病細胞と血管内皮細胞との相互作用の重要性を報告しており、血管安定性の調節による造血細胞と血管系との相互作用の制御は、白血病などの造血器腫瘍における新規治療ターゲットとなる可能性がある。

Research Products

• [Journal Article] Variable SATB1 Levels Regulate Hematopoietic Stem Cell Heterogeneity with Distinct Lineage Fate (2018)
  • Author(s): Yukiko Doi, Takafumi Yokota, Yusuke Satoh, Daisuke Okuzaki, Masahiro Tokunaga, Tomohiko Ishibashi, Takao Sudo, Tomoaki Ueda, Yasuhiro Shingai, Michiko Ichii, Akira Tanimura, Sachiko Ezoe, Hirohiko Shibayama, Terumi Kohwi-Shigematsu, Junji Takeda, Kenji Oritani, and Yuzuru Kanakura
  • Journal Title: Cell Reports Volume: 23 Issue: 11 Pages: 3223-3235
  • DOI: 10.1016/j.celrep.2018.05.042
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of MS4A3 as a reliable marker for early myeloid differentiation in human hematopoiesis. (2018)
  • Author(s): Ishibashi T, Yokota T, Satoh Y, Ichii M, Sudo T, Doi Y, Ueda T, Nagate Y, Hamanaka Y, Tanimura A, Ezoe S, Shibayama H, Oritani K, Kanakura Y.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 3 Pages: 2338-2343
  • DOI: 10.1016/j.bbrc.2017.12.117
  • Peer Reviewed / Open Access
• [Presentation] プリスタンを用いた新しい膠原病性肺高血圧症モデル作製の試み (2018)
  • Author(s): 森 啓悦, 稲垣 薫克, 石橋 知彦, 岡澤 慎, 正木 豪, 中岡 良和
  • Organizer: 第3回 日本肺高血圧・肺循環学会学術集会
• [Presentation] Cre-mediated recombination in hematopoietic lineage cells of smooth muscle cell-specific targeted Cre mice (2018)
  • Author(s): Ishibashi T, Inagaki T, Mori H, Masaki T, Asano R, Okazawa M, Nakaoka Y
  • Organizer: The 16th Korea-Japan Joint Symposium on Vasucular Biology
  • Int'l Joint Research
• [Presentation] A novel mouse model of PAH reflecting inflammation and fibrosis (2018)
  • Author(s): Mori H, Inagaki T, Ishibashi T, Okazawa M, Masaki T, Asano R, Nakaoka Y
  • Organizer: The 16th Korea-Japan Joint Symposium on Vasucular Biology
  • Int'l Joint Research
• [Presentation] TrkB might have a role for right ventricular homeostasis under chronic hypoxia-induced pulmonary hypertension (2018)
  • Author(s): Okazawa M, Inagaki T, Ishibashi T, Masaki T, Mori H, Asano R, Nakaoka Y
  • Organizer: 第2回 日本循環器学会基礎研究フォーラム
• [Presentation] Cre expression in hematopoietic cells of smooth muscle cell-targeted Cre recombination mice (2018)
  • Author(s): Ishibashi T, Inagaki T, Mori H, Masaki T, Asano R, Okazawa M, Nakaoka Y
  • Organizer: 第2回 日本循環器学会基礎研究フォーラム
• [Presentation] Pristane might be useful for creating a novel model of CTD-PAH in mice (2018)
  • Author(s): Mori H, Inagaki T, Ishibashi T, Okazawa M, Masaki T, Asano R, Nakaoka Y
  • Organizer: 第2回 日本循環器学会基礎研究フォーラム
• [Presentation] A novel mouse model of PAH reflecting inflammation and fibrosis (2018)
  • Author(s): 森 啓悦, 稲垣 薫克, 石橋 知彦, 岡澤 慎, 正木 豪, 浅野 遼太郎, 熊ノ郷 淳, 中岡 良和
  • Organizer: 第23回 日本血管病理研究会
• [Presentation] Cre recombination in hematopoietic cells of smooth muscle cell-targeted Cre recombination mice (2018)
  • Author(s): Ishibashi T, Inagaki T, Mori H, Masaki T, Okazawa M, Nakaoka Y
  • Organizer: International Vascular Biology Meeting (IVBM) 2018
  • Int'l Joint Research
• [Presentation] 平滑筋細胞特異的Creマウスの血液細胞におけるCre発現の解析 (2018)
  • Author(s): 石橋 知彦, 稲垣 薫克, 森 啓悦, 正木 豪, 浅野 遼太郎, 岡澤 慎, 中岡 良和
  • Organizer: 第26回 日本血管生物医学会学術集会 (CVMW2018)
• [Presentation] TrkB might have a role for right vascular homeostasis under chronic hypoxia-induced pulmonary hypertension in mice (2018)
  • Author(s): Okazawa M, Inagaki T, Ishibashi T, Masaki T, Mori H, Asano R, Nakaoka Y
  • Organizer: 第26回 日本血管生物医学会学術集会 (CVMW2018)
• [Presentation] A novel mouse model of connective tissue disease-associated pulmonary arterial hypertension accompanied by infiltration of inflammatory cells (2018)
  • Author(s): Mori H, Inagaki T, Ishibashi T, Okazawa M, Masaki T, Asano R, Kumanogoh A, Nakaoka Y
  • Organizer: 第26回 日本血管生物医学会学術集会 (CVMW2018)