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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • 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,
  • Keiyo Takubo

摘要

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.