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

Takayuki Morikawa, Shinya Fujita, Yuki Sugiura, Shinpei Tamaki, Miho Haraguchi, Kohei Shiroshita, Shintaro Watanuki, Hiroshi Kobayashi, Hikari Kanai-Sudo, Yoshiko Naito, Noriyo Hayakawa, Tomomi Matsuura, Takako Hishiki, Minoru Matsui, Masato Tsutsui, Makoto Suematsu and Keiyo Takubo ()
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Takayuki Morikawa: Japan Institute for Health Security
Shinya Fujita: Japan Institute for Health Security
Yuki Sugiura: Kyoto University Graduate School of Medicine
Shinpei Tamaki: Japan Institute for Health Security
Miho Haraguchi: Japan Institute for Health Security
Kohei Shiroshita: Japan Institute for Health Security
Shintaro Watanuki: Japan Institute for Health Security
Hiroshi Kobayashi: Japan Institute for Health Security
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
Keiyo Takubo: Japan Institute for Health Security

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60515-9

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