Elucidation of aging process of bone marrow niche by intravital imaging

• Project/Area Number: 18K08379
• 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: National Center for Global Health and Medicine
• Principal Investigator: Morikawa Takayuki 国立研究開発法人国立国際医療研究センター, その他部局等, 研究員 (80465012)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 造血幹細胞 / 骨髄 / 生体イメージング / ニッチ / 微小循環

Outline of Final Research Achievements

It is suggested that hematopoietic stem cells are retained in the bone marrow niche in many adult mammals. In this study, we revealed how hematopoietic stem cell niche is changing with aging. The result of metabolome analysis showed that some signaling pathways were downregulated in aged mouse bone marrow. We validated one of the metabolites involved in these pathway is synthesized in vascular endothelial cells of bone marrow by immunohistochemistry. Using intravital imaging analysis, we also observed that this metabolite maintains bone marrow blood flow and facilitates transendothelial migration of hematopoietic stem progenitor cells in bone marrow. These results indicate that low homing efficiency of hematopoietic stem cells in aged bone marrow is caused by decreased NO production in stem cell niche.

Academic Significance and Societal Importance of the Research Achievements

本研究で得られた加齢に伴う造血幹細胞ニッチの代謝動態の変容を示す知見から、これまで未解明であった造血幹細胞移植における加齢による生着率の低下の機序の全貌を明らかにすることのできる成果に結びつく学術的意義を持つと考えられる。また本研究成果の社会的意義としては、本研究成果を多くの血液疾患において重要な治療法である造血幹細胞移植の適応年齢の拡大に結びつく知見へと発展させることで、高齢化社会に十分に適応した医療体制の拡充に寄与する可能性があることなどがあげられる。

Research Products

• [Journal Article] p38α plays differential roles in hematopoietic stem cell activity dependent on aging contexts (2021)
  • Author(s): Sorimachi Yuriko、Karigane Daiki、Ootomo Yukako、Kobayashi Hiroshi、Morikawa Takayuki、Otsu Kinya、Kubota Yoshiaki、Okamoto Shinichiro、Goda Nobuhito、Takubo Keiyo
  • Journal Title: Journal of Biological Chemistry Volume: 296 Pages: 100563-100563
  • DOI: 10.1016/j.jbc.2021.100563
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification and local manipulation of bone marrow vasculature during intravital imaging (2020)
  • Author(s): Morikawa Takayuki、Tamaki Shinpei、Fujita Shinya、Suematsu Makoto、Takubo Keiyo
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 6422-6422
  • DOI: 10.1038/s41598-020-63533-3
  • Peer Reviewed / Open Access
• [Journal Article] Potential involvement of semaphorin 3A in maintaining intervertebral disc tissue homeostasis (2019)
  • Author(s): Mima Y, Suzuki S, Fujii T, Morikawa T, Tamaki S, Takubo K, Shimoda M, Miyamoto T, Watanabe K, Matsumoto M, Nakamura M, Fujita N.
  • Journal Title: J Orthop Res Volume: 37 Issue: 4 Pages: 972-980
  • DOI: 10.1002/jor.24258
  • Peer Reviewed / Open Access
• [Journal Article] Environmental Optimization Enables Maintenance of Quiescent Hematopoietic Stem Cells Ex Vivo. (2019)
  • Author(s): Kobayashi H, Morikawa T, Okinaga A, Hamano F, Hashidate-Yoshida T, Watanuki S, Hishikawa D, Shindou H, Arai F, Kabe Y, Suematsu M, Shimizu T, Takubo K.
  • Journal Title: Cell Reports Volume: 28 Issue: 1 Pages: 145-158
  • DOI: 10.1016/j.celrep.2019.06.008
  • Peer Reviewed / Open Access
• [Journal Article] Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses (2019)
  • Author(s): Nagai M、Noguchi R、Takahashi D、Morikawa T、Koshida K、Komiyama S、Ishihara N、Yamada T、Kawamura YI.、Muroi K、Hattori K、Kobayashi N、Fujimura Y、Hirota M、Matsumoto R、Aoki R、Tamura-Nakano M、Sugiyama M、Katakai T、Sato S、Takubo K、Dohi T、Hase K
  • Journal Title: Cell Volume: 178 Issue: 5 Pages: 1072-1087
  • DOI: 10.1016/j.cell.2019.07.047
  • Peer Reviewed
• [Journal Article] Quantitative imaging mass spectroscopy reveals roles of heme oxygenase-2 for protecting against transhemispheric diaschisis in the brain ischemia (2018)
  • Author(s): 1.Shinichi Goto, Takayuki Morikawa, Akiko Kubo, Keiyo Takubo, Keiichi Fukuda, Mayumi Kajimura, Makoto Suematsu
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 63 Issue: 1 Pages: 70-79
  • DOI: 10.3164/jcbn.17-136
  • NAID: 130007387127
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Journal Article] Gold-nanofève surface-enhanced Raman spectroscopy visualizes hypotaurine as a robust anti-oxidant consumed in cancer survival (2018)
  • Author(s): Shiota M, Naya M, Yamamoto T, Hishiki T, Tani T, Takahashi H, Kubo A, Koike D, Itoh M, Ohmura M, Kabe Y, Sugiura Y, Hiraoka N, Morikawa T, Takubo K, Suina K, Nagashima H, Sampetrean O, Nagano O, Saya H, Yamazoe S, Watanabe H, Suematsu M
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1561-1561
  • DOI: 10.1038/s41467-018-03899-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Age-related alteration in nitric oxide signaling attenuates arrival of transplanted hematopoietic stem/progenitor cells to bone marrow (2018)
  • Author(s): Takayuki Morikawa、Keiyo Takubo
  • Organizer: 幹細胞シンポジウム
• [Presentation] Aging impairs NO-mediated migration of transplanted hematopoietic stem/progenitors to bone marrow (2018)
  • Author(s): Takayuki Morikawa、Keiyo Takubo
  • Organizer: 日本血液学会