IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-60515-9.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-60515-9
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-60515-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.
    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. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yang Liu & Qi Chen & Hyun-Woo Jeong & Bong Ihn Koh & Emma C. Watson & Cong Xu & Martin Stehling & Bin Zhou & Ralf H. Adams, 2022. "A specialized bone marrow microenvironment for fetal haematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Raymond K. H. Yip & Joel S. Rimes & Bianca D. Capaldo & François Vaillant & Kellie A. Mouchemore & Bhupinder Pal & Yunshun Chen & Elliot Surgenor & Andrew J. Murphy & Robin L. Anderson & Gordon K. Smy, 2021. "Mammary tumour cells remodel the bone marrow vascular microenvironment to support metastasis," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    3. Young-Woong Kim & Greta Zara & HyunJun Kang & Sergio Branciamore & Denis O’Meally & Yuxin Feng & Chia-Yi Kuan & Yingjun Luo & Michael S. Nelson & Alex B. Brummer & Russell Rockne & Zhen Bouman Chen & , 2022. "Integration of single-cell transcriptomes and biological function reveals distinct behavioral patterns in bone marrow endothelium," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    4. Alexandra N. Rindone & Xiaonan Liu & Stephanie Farhat & Alexander Perdomo-Pantoja & Timothy F. Witham & Daniel L. Coutu & Mei Wan & Warren L. Grayson, 2021. "Quantitative 3D imaging of the cranial microvascular environment at single-cell resolution," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    5. Joschka Heil & Victor Olsavszky & Katrin Busch & Kay Klapproth & Carolina Torre & Carsten Sticht & Kajetan Sandorski & Johannes Hoffmann & Hiltrud Schönhaber & Johanna Zierow & Manuel Winkler & Christ, 2021. "Bone marrow sinusoidal endothelium controls terminal erythroid differentiation and reticulocyte maturation," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    6. Runfeng Miao & Harim Chun & Xing Feng & Ana Cordeiro Gomes & Jungmin Choi & João P. Pereira, 2022. "Competition between hematopoietic stem and progenitor cells controls hematopoietic stem cell compartment size," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    7. Qiang Zhao & Young-Min Han & Ping Song & Zhixue Liu & Zuyi Yuan & Ming-Hui Zou, 2022. "Endothelial cell-specific expression of serine/threonine kinase 11 modulates dendritic cell differentiation," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    8. Haoqing Jerry Wang & Yao Wang & Seyed Sajad Mirjavadi & Tomas Andersen & Laura Moldovan & Parham Vatankhah & Blake Russell & Jasmine Jin & Zijing Zhou & Qing Li & Charles D. Cox & Qian Peter Su & Lini, 2024. "Microscale geometrical modulation of PIEZO1 mediated mechanosensing through cytoskeletal redistribution," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    9. Jialiang S. Wang & Tushar Kamath & Courtney M. Mazur & Fatemeh Mirzamohammadi & Daniel Rotter & Hironori Hojo & Christian D. Castro & Nicha Tokavanich & Rushi Patel & Nicolas Govea & Tetsuya Enishi & , 2021. "Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    10. Yingchao Xue & Elizabeth Winnicki & Zhaoxu Zhang & Ines Lopez & Saifeng Wang & Charles Kirby & Sam S. Lee & Ang Li & Chaewon Lee & Hana Minsky & Kaitlin Williams & Kevin Yueh-Hsun Yang & Ling He & Sas, 2025. "The mechanotransducer Piezo1 coordinates metabolism and inflammation to promote skin growth," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    11. Yang Li & Nan Li & Wei Liu & Aleksander Prominski & Seounghun Kang & Yahao Dai & Youdi Liu & Huawei Hu & Shinya Wai & Shilei Dai & Zhe Cheng & Qi Su & Ping Cheng & Chen Wei & Lihua Jin & Jeffrey A. Hu, 2023. "Achieving tissue-level softness on stretchable electronics through a generalizable soft interlayer design," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    12. Thomas H. Ambrosi & David Morales & Kun Chen & Ethan J. Hunt & Kelly C. Weldon & Amber N. Maifeld & Fatima I. M. Chavez & Yuting Wang & Liming Zhao & Luke Wang & Matthew P. Murphy & Amin Cressman & Er, 2025. "Basigin links altered skeletal stem cell lineage dynamics with glucocorticoid-induced bone loss and impaired angiogenesis," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    13. Tiago C. Luis & Nikolaos Barkas & Joana Carrelha & Alice Giustacchini & Stefania Mazzi & Ruggiero Norfo & Bishan Wu & Affaf Aliouat & Jose A. Guerrero & Alba Rodriguez-Meira & Tiphaine Bouriez-Jones &, 2023. "Perivascular niche cells sense thrombocytopenia and activate hematopoietic stem cells in an IL-1 dependent manner," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. Alicia Villatoro & Vincent Cuminetti & Aurora Bernal & Carlos Torroja & Itziar Cossío & Alberto Benguría & Marc Ferré & Joanna Konieczny & Enrique Vázquez & Andrea Rubio & Peter Utnes & Almudena Tello, 2023. "Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation," Nature Communications, Nature, vol. 14(1), pages 1-28, December.
    15. Naoki Itokawa & Motohiko Oshima & Shuhei Koide & Naoya Takayama & Wakako Kuribayashi & Yaeko Nakajima-Takagi & Kazumasa Aoyama & Satoshi Yamazaki & Kiyoshi Yamaguchi & Yoichi Furukawa & Koji Eto & Ats, 2022. "Epigenetic traits inscribed in chromatin accessibility in aged hematopoietic stem cells," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    16. Trent D. Hall & Hyunjin Kim & Mahmoud Dabbah & Jacquelyn A. Myers & Jeremy Chase Crawford & Antonio Morales-Hernandez & Claire E. Caprio & Pramika Sriram & Emilia Kooienga & Marta Derecka & Esther A. , 2022. "Murine fetal bone marrow does not support functional hematopoietic stem and progenitor cells until birth," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    17. Yoshito Yamada & Tuan Thanh Nguyen & Daniela Impellizzieri & Katsutaka Mineura & Rintaro Shibuya & Alvaro Gomariz & Martina Haberecker & Jakob Nilsson & César Nombela-Arrieta & Wolfgang Jungraithmayr , 2023. "Biased IL-2 signals induce Foxp3-rich pulmonary lymphoid structures and facilitate long-term lung allograft acceptance in mice," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    18. Sergei Butenko & Raji R. Nagalla & Christian F. Guerrero-Juarez & Francesco Palomba & Li-Mor David & Ronald Q. Nguyen & Denise Gay & Axel A. Almet & Michelle A. Digman & Qing Nie & Philip O. Scumpia &, 2024. "Hydrogel crosslinking modulates macrophages, fibroblasts, and their communication, during wound healing," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    19. Till Fabian Mertens & Alina Tabea Liebheit & Johanna Ehl & Ralf Köhler & Asylkhan Rakhymzhan & Andrew Woehler & Lukas Katthän & Gernot Ebel & Wjatscheslaw Liublin & Ana Kasapi & Antigoni Triantafyllop, 2024. "MarShie: a clearing protocol for 3D analysis of single cells throughout the bone marrow at subcellular resolution," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    20. Adrienne Anginot & Julie Nguyen & Zeina Abou Nader & Vincent Rondeau & Amélie Bonaud & Maria Kalogeraki & Antoine Boutin & Julia P. Lemos & Valeria Bisio & Joyce Koenen & Lea Hanna Doumit Sakr & Amand, 2023. "WHIM Syndrome-linked CXCR4 mutations drive osteoporosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60515-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.