The mechanism of organelle relocation in human erythroblasts.

• Project/Area Number: 18K08315
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Akita University
• Principal Investigator: Ubukawa Kumi 秋田大学, 医学系研究科, 講師 (70646554)
• Co-Investigator(Kenkyū-buntansha): 高橋 直人 秋田大学, 医学系研究科, 教授 (80344753)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ヒト赤芽球 / 脱核 / Cdc42 / 造血幹細胞 / 好中球 / LPS / TRL4 / CASIN（阻害剤） / CASIN / 赤血球造血

Outline of Final Research Achievements

The molecular mechanisms involved in the terminal differentiation of erythroblasts have been elucidated by comparing enucleation and cell division.
We herein investigated the effects of the cell division control protein 42 homolog (Cdc42) inhibitor, CASIN, on cytokinesis and enucleation in colony-forming units-erythroid (CFU-Es) and mature erythroblasts (day 10). CASIN blocked the proliferation of CFU-Es and their enucleation in a dose-dependent manner. Dynein adopted an island-like distribution in the cytoplasm of non-treated CFU-Es, but was concentrated near the nucleus as a dot and co-localized with γ-tubulin in CASIN-treated cells. CASIN blocked the accumulation of F-actin in CFU-Es and day 10 cells.
These results demonstrated that Cdc42 plays an important role in cytokinesis, nuclear polarization and nuclear extrusion through a relationship with dynein and actin filament organization during the terminal differentiation of erythroblasts.

Academic Significance and Societal Importance of the Research Achievements

ヒト赤芽球の分化、特に脱核時にCdc42が重要な役割を担うことを初めて示し、通常の細胞分裂と赤芽球脱核の類似点と相違点をまた一つ明らかにしたことに学術的意義がある。
社会的意義としては、赤血球の工業的産生への応用や疾患の病態解明があげられる。iPS細胞を用いた人工的赤血球産生においては、低い脱核率が問題となっており、赤芽球脱核のメカニズムを明らかにする本研究は、この問題点を解決する一助となる可能性がある。また、Cdc42阻害を含む細胞質分裂阻害剤が引き起こす赤芽球形態の異常は骨髄異形成症候群の赤芽球形態と類似点があり、病態解明に結び付く可能性がある。

Research Products

• [Journal Article] IL-6 Generated from Human Hematopoietic Stem and Progenitor Cells through TLR4 Signaling Promotes Emergency Granulopoiesis by Regulating Transcription Factor Expression (2021)
  • Author(s): Sasaki Yumi、Guo Yong-Mei、Goto Tatsufumi、Ubukawa Kumi、Asanuma Ken、Kobayashi Isuzu、Sawada Kenichi、Wakui Hideki、Takahashi Naoto
  • Journal Title: The Journal of Immunology Volume: 207 Issue: 4 Pages: 1078-1086
  • DOI: 10.4049/jimmunol.2100168
  • Peer Reviewed
• [Journal Article] Cdc42 regulates cell polarization and contractile actomyosin rings during terminal differentiation of human erythroblasts (2020)
  • Author(s): Ubukawa Kumi、Goto Tatsufumi、Asanuma Ken、Sasaki Yumi、Guo Yong-Mei、Kobayashi Isuzu、Sawada Kenichi、Wakui Hideki、Takahashi Naoto
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 11806-11806
  • DOI: 10.1038/s41598-020-68799-1
  • Peer Reviewed / Open Access
• [Journal Article] Thrombocytopenia Caused by a Tea Beverage of <i>Taxus yunnanensis</i> (Chinese Yew) (2019)
  • Author(s): Ubukawa K, Kameoka Y, Guo YM, Nara M, Watanabe A, Fujishima M, Fujishima N, Yoshioka T, Takahashi N.
  • Journal Title: Internal Medicine Volume: 58 Issue: 21 Pages: 3153-3156
  • DOI: 10.2169/internalmedicine.2967-19
  • NAID: 130007740721
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-11-01
  • Peer Reviewed / Open Access
• [Journal Article] 1.ATP produced by anaerobic glycolysis is essential for enucleation of human erythroblasts. (2019)
  • Author(s): Goto T, Ubukawa K, Kobayashi I, Sugawara K, Asanuma K, Sasaki Y, Guo YM, Takahashi N, Sawada K, Wakui H, Nunomura W.
  • Journal Title: Exp Hematol. Volume: 72
  • Peer Reviewed / Open Access
• [Journal Article] The localization of α-synuclein in the process of differentiation of human erythroid cells (2018)
  • Author(s): Araki Katsuya、Sugawara Kotomi、Hayakawa Eri H.、Ubukawa Kumi、Kobayashi Isuzu、Wakui Hideki、Takahashi Naoto、Sawada Kenichi、Mochizuki Hideki、Nunomura Wataru
  • Journal Title: International Journal of Hematology Volume: 108 Issue: 2 Pages: 130-138
  • DOI: 10.1007/s12185-018-2457-8
  • Peer Reviewed
• [Journal Article] 赤血球脱核とその異常 (2018)
  • Author(s): 鵜生川久美
  • Journal Title: 血液フロンティア Volume: 28 Pages: 1315-1359
• [Presentation] Cdc42 regulates terminal differentiation in human erythroblasts. (2018)
  • Author(s): Goto T, Ubukawa K, Asanuma K, Kobayashi I, Guo YM, Takahashi N, Wakui H, Nunomura W.
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] ヒト赤芽球の終末分化におけるCdc42の情報伝達経路の解明． (2018)
  • Author(s): 後藤樹史、鵜生川久美、浅沼研、小林五十鈴、郭永梅、高橋直人、涌井秀樹、布村渉
  • Organizer: 第91回日本生化学会学術集会