Essential roles of embryo-specific hypoxic microenvironments for organizing primitive erythropoiesis and morphogenesis

• Project/Area Number: 22K19396
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: Tohoku University
• Principal Investigator: Suzuki Norio 東北大学, 未来科学技術共同研究センター, 教授 (20447254)
• Project Period (FY): 2022-06-30 – 2025-03-31
• Project Status: Completed (Fiscal Year 2024)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2023: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2022: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 酸素 / 個体発生 / 遺伝子改変マウス / 赤血球造血

Outline of Research at the Start

血液循環系が成立するまでの初期胚では、酸素供給は胚周辺の溶存酸素の拡散に依存しているため、赤血球を介した効率的な酸素供給ができない。そのうえ、初期胚は細胞増殖や細胞移動に大量の酸素を消費するため、初期胚は全体的に重篤な低酸素状態に陥っている。本年度は、循環系成立前後のマウス胚を主な解析対象として、胚内酸素分布を明らかにする。また、低酸素領域においてHIFが活性化して赤血球造血因子産生を誘導することを示す。

Outline of Final Research Achievements

Since oxygen molecules (O2) are essential for animal cells, a lack of O2 (hypoxia) induces serious stress. Until the circulatory system is established in developing embryos, the efficiency of O2 supply is low, leading to hypoxic microenvironments within the embryos. This study, using mice, demonstrated that these embryo-specific hypoxic microenvironments are utilized as cellular signals during development. Additionally, we discovered that hypoxic conditions are also employed to maintain undifferentiated states and to produce growth factors in rat and human neural cells. These findings suggest that certain cells actively utilize hypoxic conditions as cellular signals rather than perceiving them as stress.

Academic Significance and Societal Importance of the Research Achievements

低酸素状態が個体発生を調節するシグナルとして機能することを示し、形成体（organizer）による形態形成誘導という発生学の古典的な概念に新展開をもたらした。また、低酸素状態をストレスとして捉えてきた従来の考えに対して逆説的な生命現象を提唱した。今後、胎児期の酸素環境に対する理解が進むことにより、母体の生活環境が胎児に及ぼす影響も明らかになると期待される。

Research Products

• [Int'l Joint Research] Karolinska Institute(スウェーデン)
  • Country Name: SWEDEN
  • Counterpart Institution: Karolinska Institute
• [Journal Article] Erythropoietin Production in Embryonic Neural Cells is Controlled by Hypoxia Signaling and Histone Deacetylases with an Undifferentiated Cellular State (2024)
  • Author(s): Iwamura Yuma、Nakai Taku、Kato Koichiro、Ishioka Hirotaka、Yamamoto Masayuki、Hirano Ikuo、Suzuki Norio
  • Journal Title: Molecular and Cellular Biology Volume: 45 Pages: 32～45
  • DOI: 10.1080/10985549.2024.2428717
  • Peer Reviewed / Open Access
• [Journal Article] The drug-specific properties of hypoxia-inducible factor-prolyl hydroxylase inhibitors in mice reveal a significant contribution of the kidney compared to the liver to erythropoietin induction (2024)
  • Author(s): Nakai Taku、Saigusa Daisuke、Kato Koichiro、Fukuuchi Tomoko、Koshiba Seizo、Yamamoto Masayuki、Suzuki Norio
  • Journal Title: Life Sciences Volume: 346 Pages: 122641～122641
  • DOI: 10.1016/j.lfs.2024.122641
  • Peer Reviewed / Open Access
• [Journal Article] PNPO?PLP axis senses prolonged hypoxia in macrophages by regulating lysosomal activity (2024)
  • Author(s): Sekine H, Takeda H, Takeda N, Kishino A, Anzawa H, Isagawa T, Ohta N, Murakami S, Iwaki H, Kato N, Kimura S, Liu Z, Kato K, Katsuoka F, Yamamoto M, Miura F, Ito T, Takahashi M, Izumi Y, Fujita H, Yamagata H, Bamba T, Akaike T, Suzuki N, Kinoshita K, Motohashi H
  • Journal Title: Nature Metabolism Volume: 6 Pages: 1108～1127
  • DOI: 10.1038/s42255-024-01053-4
  • Peer Reviewed / Open Access
• [Journal Article] Crosstalk between oxygen signaling and iron metabolism in renal interstitial fibroblasts (2024)
  • Author(s): Suzuki Norio、Iwamura Yuma、Kato Koichiro、Ishioka Hirotaka、Konta Yusuke、Sato Koji、Uchida Nao、Koida Noa、Sekine Hiroki、Tanaka Tetsuhiro、Kumagai Naonori、Nakai Taku
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 74 Pages: 179～184
  • DOI: 10.3164/jcbn.24-8
  • Peer Reviewed
• [Journal Article] Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice (2023)
  • Author(s): Nakai Taku、Iwamura Yuma、Kato Koichiro、Hirano Ikuo、Matsumoto Yotaro、Tomioka Yoshihisa、Yamamoto Masayuki、Suzuki Norio
  • Journal Title: Blood Advances Volume: 7 Pages: 3793-3805
  • DOI: 10.1182/bloodadvances.2023009798
  • Peer Reviewed / Open Access
• [Journal Article] Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice (2023)
  • Author(s): Shimizu Ritsuko、Hirano Ikuo、Hasegawa Atsushi、Suzuki Mikiko、Otsuki Akihito、Taguchi Keiko、Katsuoka Fumiki、Uruno Akira、Suzuki Norio、Yumoto Akane、Okada Risa、Shirakawa Masaki、Shiba Dai、Takahashi Satoru、Suzuki Takafumi、Yamamoto Masayuki
  • Journal Title: Communications Biology Volume: 6 Pages: 875
  • DOI: 10.1038/s42003-023-05251-w
  • Peer Reviewed / Open Access
• [Journal Article] 腎臓病と低酸素応答機構 (2023)
  • Author(s): 石岡広崇, 鈴木教郎
  • Journal Title: 腎臓内科 Volume: 17 Pages: 714-720
• [Journal Article] Improving lipophilicity of 5-(1-acetyl-5-phenylpyrazolidin-3-ylidene)-1,3-dimethylbarbituric acid increases its efficacy to activate hypoxia-inducible factors (2022)
  • Author(s): Sonoda Kento、Ujike Saki、Katayama Akito、Suzuki Norio、Kawaguchi Shin-ichi、Tsujita Tadayuki
  • Journal Title: Bioorganic and Medicinal Chemistry Volume: 73 Pages: 117039～117039
  • DOI: 10.1016/j.bmc.2022.117039
  • Peer Reviewed / Open Access
• [Journal Article] Prolyl Hydroxylase Domain Protein Inhibitor Not Harboring a 2-Oxoglutarate Scaffold Protects against Hypoxic Stress (2022)
  • Author(s): Sonoda Kento、Bogahawaththa Sudarma、Katayama Akito、Ujike Saki、Kuroki Sae、Kitagawa Naho、Hirotsuru Kohichi、Suzuki Norio、Miyata Toshio、Kawaguchi Shin-ichi、Tsujita Tadayuki
  • Journal Title: ACS Pharmacology and Translational Science Volume: 5 Pages: 362～372
  • DOI: 10.1021/acsptsci.2c00002
  • Peer Reviewed / Open Access
• [Journal Article] Esterification promotes the intracellular accumulation of roxadustat, an activator of hypoxia-inducible factors, to extend its effective duration (2022)
  • Author(s): Nakai Taku、Saigusa Daisuke、Iwamura Yuma、Matsumoto Yotaro、Umeda Keiko、Kato Koichiro、Yamaki Hayato、Tomioka Yoshihisa、Hirano Ikuo、Koshiba Seizo、Yamamoto Masayuki、Suzuki Norio
  • Journal Title: Biochemical Pharmacology Volume: 197 Pages: 114939～114939
  • Peer Reviewed / Open Access
• [Journal Article] 腎性貧血と酸素ホメオスタシス (2022)
  • Author(s): 岩村悠真, 鈴木教郎
  • Journal Title: 腎と透析 Volume: 93 Pages: 751-755
  • Peer Reviewed
• [Journal Article] HIF-PH阻害薬による赤血球造血誘導と鉄利用促進の分子機構 (2022)
  • Author(s): 中井琢, 鈴木教郎
  • Journal Title: 腎と透析 Volume: 93 Pages: 179-183
  • Peer Reviewed
• [Presentation] 低酸素誘導性因子活性化剤HIF-PHIの薬剤特異的赤血球造血促進機構 (2025)
  • Author(s): 鈴木教郎
  • Organizer: 日本解剖生理薬理合同学会APPW2025
  • Invited
• [Presentation] 腎臓における低酸素・酸化ストレス応答系の役割とその破綻による疾患発生機序 (2024)
  • Author(s): 鈴木教郎
  • Organizer: 第77回 日本酸化ストレス学会
  • Invited
• [Presentation] HIF-PH阻害薬による赤血球造血誘導のメカニズム (2024)
  • Author(s): 鈴木教郎
  • Organizer: 日本腎臓学会
  • Invited
• [Presentation] 低酸素センサー特異的2-OGアナログ阻害剤（HIF-PH阻害薬）による赤血球造血誘導の分子機構 (2024)
  • Author(s): 鈴木教郎
  • Organizer: 第97回日本生化学会大会
  • Invited
• [Presentation] Identification of the proper subset responsible for erythropoietin production among renal fibroblasts (2024)
  • Author(s): Taku Nakai, Norio Suzuki
  • Organizer: HypoxEU Live Programme
  • Int'l Joint Research
• [Presentation] Hypoxia signaling and histone deacetylases govern developmental stage-specific erythropoietin production in embryonic neural cells (2024)
  • Author(s): Yuma Iwamura, Taku Nakai, Koichiro Kato, Hirotaka Ishioka, Masayuki Yamamoto, Ikuo Hirano, Norio Suzuki
  • Organizer: HypoxEU Live Programme
  • Int'l Joint Research
• [Presentation] 個体発生に伴うエリスロポエチン産生制御機構の変遷 (2023)
  • Author(s): 鈴木教郎
  • Organizer: 赤血球研究シンポジウム
  • Invited
• [Presentation] 宇宙旅行による骨量および血圧の変動における腎臓の貢献 (2023)
  • Author(s): 鈴木教郎
  • Organizer: 第66回日本腎臓学会学術総会
  • Invited
• [Presentation] 宇宙微小重力環境を利用した腎機能の加齢変化の解析 (2023)
  • Author(s): 鈴木教郎
  • Organizer: 第53 回日本腎臓学会東部学術大会
  • Invited
• [Presentation] 糖化ストレスに対する酸化ストレス防御系の役割 (2023)
  • Author(s): 鈴木教郎
  • Organizer: 第33 回日本メイラード学会年会
  • Invited
• [Presentation] Hypoxia inducible factor 2 alpha and histone deacetylases control erythroid growth factor in embryonic neural cells with their development (2023)
  • Author(s): Iwamura Y, Nakai T, Kato K, Ishioka H, Yamamoto M, Hirano I, Suzuki N
  • Organizer: KEYSTONE SYMPOSIA
  • Int'l Joint Research
• [Presentation] Pharmacological activation of hypoxia-inducible factors promotes erythropoiesis and suppresses hepcidin production by inducing erythropoietin production in the kidneys (2023)
  • Author(s): Nakai T, Iwamura Y, Kato K, Hirano I, Matsumoto Y, Tomioka Y, Yamamoto M, Suzuki N
  • Organizer: KEYSTONE SYMPOSIA
  • Int'l Joint Research
• [Presentation] A subpopulation of renal interstitial fibroblasts originates from embryonic neural cells that produce the erythroid growth factor erythropoietin (2023)
  • Author(s): Iwamura Y, Nakai T, Kato K, Ishioka H, Yamamoto M, Hirano I, Suzuki N
  • Organizer: The 56th Annual Meeting of the Japanese Society of Developmental Biologists
  • Int'l Joint Research
• [Presentation] 胎仔期神経系細胞特異的な赤血球造血因子エリスロポエチンの産生制御機構 (2023)
  • Author(s): 岩村悠真, 中井琢，石岡広崇, 加藤幸一郎，鈴木教郎
  • Organizer: 第96回日本生化学会大会
• [Presentation] 個体レベルの低酸素応答機構解析系と貧血モデル動物 (2023)
  • Author(s): 鈴木教郎
  • Organizer: 第96回日本生化学会大会
• [Presentation] 低酸素誘導性転写因子HIF2aとヒストン脱アセチル化酵素による胎児期神経系細胞のエリスロポエチン産生制御機構 (2022)
  • Author(s): 岩村悠真, 中井琢，加藤幸一郎，鈴木教郎
  • Organizer: 日本生化学会 東北支部 第88回例会
• [Presentation] 胎仔期神経系細胞における低酸素誘導的・発生段階特異的エリスロポエチン産生制御機構 (2022)
  • Author(s): 岩村悠真, 中井琢，加藤幸一郎, 鈴木教郎
  • Organizer: 低酸素研究会2022
• [Presentation] 胎仔期神経系細胞における発生段階特異的な赤血球造血因子エリスロポエチン産生制御機構 (2022)
  • Author(s): 岩村悠真, 中井琢，加藤幸一郎, 鈴木教郎
  • Organizer: 第45回日本分子生物学会