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Decreased non-neurogenic acetylcholine in bone marrow triggers age-related defective stem/progenitor cell homing

Author

Listed:
  • Takayuki Morikawa

    (Japan Institute for Health Security)

  • Shinya Fujita

    (Japan Institute for Health Security)

  • Yuki Sugiura

    (Kyoto University Graduate School of Medicine
    Keio University)

  • Shinpei Tamaki

    (Japan Institute for Health Security)

  • Miho Haraguchi

    (Japan Institute for Health Security
    Kanagawa Institute of Industrial Science and Technology (KISTEC))

  • Kohei Shiroshita

    (Japan Institute for Health Security)

  • Shintaro Watanuki

    (Japan Institute for Health Security
    Tohoku University Graduate School of Medicine)

  • Hiroshi Kobayashi

    (Japan Institute for Health Security
    Tohoku University Graduate School of Medicine)

  • Hikari Kanai-Sudo

    (Japan Institute for Health Security)

  • Yoshiko Naito

    (Keio University Hospital)

  • Noriyo Hayakawa

    (Central Institute for Experimental Medicine and Life Science)

  • Tomomi Matsuura

    (Keio University Hospital)

  • Takako Hishiki

    (Machida)

  • Minoru Matsui

    (Yokokawa Ladies Clinic)

  • Masato Tsutsui

    (University of the Ryukyus)

  • Makoto Suematsu

    (Keio University
    Central Institute for Experimental Medicine and Life Science)

  • Keiyo Takubo

    (Japan Institute for Health Security
    Tohoku University Graduate School of Medicine
    Core Research for Evolutional Science and Technology (CREST))

Abstract

Age-related decline in the ability of bone marrow (BM) to recruit transplanted hematopoietic stem and progenitor cells (HSPCs) limits the potential of HSPC-based medicine. Using in vivo imaging and manipulation combined with integrative metabolomic analyses, we show that, with aging, degradation of non-neurogenic acetylcholine disrupts the local Chrm5-eNOS-nitric oxide signaling, reducing arterial dilation and decreasing both BM blood flow and sinusoidal wall shear stress. Consequently, aging BM microenvironment impairs transendothelial migration of transplanted HSPCs, and their BM homing efficiency is reduced, mediated by decreased activation of Piezo1. Notably, pharmacological activation of Piezo1 improves HSPC homing efficiency and post-transplant survival of aged recipients. These findings suggest that age-related dysregulation of local arteries leads to impaired HSPC homing to BM by decreasing shear stress. Modulation of these mechanisms may improve the efficacy and safety of clinical transplantation in elderly patients.

Suggested Citation

  • Takayuki Morikawa & Shinya Fujita & Yuki Sugiura & Shinpei Tamaki & Miho Haraguchi & Kohei Shiroshita & Shintaro Watanuki & Hiroshi Kobayashi & Hikari Kanai-Sudo & Yoshiko Naito & Noriyo Hayakawa & To, 2025. "Decreased non-neurogenic acetylcholine in bone marrow triggers age-related defective stem/progenitor cell homing," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60515-9
    DOI: 10.1038/s41467-025-60515-9
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    as
    1. Kazuhiro Furuhashi & Miwako Kakiuchi & Ryosuke Ueda & Hiroko Oda & Simone Ummarino & Alexander K. Ebralidze & Mahmoud A. Bassal & Chen Meng & Tatsuyuki Sato & Jing Lyu & Min-guk Han & Shoichi Maruyama, 2025. "Bone marrow niches orchestrate stem-cell hierarchy and immune tolerance," Nature, Nature, vol. 638(8049), pages 206-215, February.
    2. Yang Mei & Xu Han & Yijie Liu & Jing Yang & Ronen Sumagin & Peng Ji, 2020. "Diaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    3. Dorothy A. Sipkins & Xunbin Wei & Juwell W. Wu & Judith M. Runnels & Daniel Côté & Terry K. Means & Andrew D. Luster & David T. Scadden & Charles P. Lin, 2005. "In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment," Nature, Nature, vol. 435(7044), pages 969-973, June.
    4. Yuya Kunisaki & Ingmar Bruns & Christoph Scheiermann & Jalal Ahmed & Sandra Pinho & Dachuan Zhang & Toshihide Mizoguchi & Qiaozhi Wei & Daniel Lucas & Keisuke Ito & Jessica C. Mar & Aviv Bergman & Pau, 2013. "Arteriolar niches maintain haematopoietic stem cell quiescence," Nature, Nature, vol. 502(7473), pages 637-643, October.
    5. Cristina Lo Celso & Heather E. Fleming & Juwell W. Wu & Cher X. Zhao & Sam Miake-Lye & Joji Fujisaki & Daniel Côté & David W. Rowe & Charles P. Lin & David T. Scadden, 2009. "Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche," Nature, Nature, vol. 457(7225), pages 92-96, January.
    6. Anjali P. Kusumbe & Saravana K. Ramasamy & Tomer Itkin & Maarja Andaloussi Mäe & Urs H. Langen & Christer Betsholtz & Tsvee Lapidot & Ralf H. Adams, 2016. "Age-dependent modulation of vascular niches for haematopoietic stem cells," Nature, Nature, vol. 532(7599), pages 380-384, April.
    7. Chunliang Xu & Xin Gao & Qiaozhi Wei & Fumio Nakahara & Samuel E. Zimmerman & Jessica Mar & Paul S. Frenette, 2018. "Stem cell factor is selectively secreted by arterial endothelial cells in bone marrow," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    8. Alvaro Gomariz & Patrick M. Helbling & Stephan Isringhausen & Ute Suessbier & Anton Becker & Andreas Boss & Takashi Nagasawa & Grégory Paul & Orcun Goksel & Gábor Székely & Szymon Stoma & Simon F. Nør, 2018. "Quantitative spatial analysis of haematopoiesis-regulating stromal cells in the bone marrow microenvironment by 3D microscopy," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    9. Claire Fielding & Andrés García-García & Claudia Korn & Stephen Gadomski & Zijian Fang & Juan L. Reguera & José A. Pérez-Simón & Berthold Göttgens & Simón Méndez-Ferrer, 2022. "Cholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    10. Hamza Atcha & Amit Jairaman & Jesse R. Holt & Vijaykumar S. Meli & Raji R. Nagalla & Praveen Krishna Veerasubramanian & Kyle T. Brumm & Huy E. Lim & Shivashankar Othy & Michael D. Cahalan & Medha M. P, 2021. "Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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