Morikawa Takayuki, Fujita Shinya, Sugiura Yuki, Tamaki Shinpei, Haraguchi Miho, Shiroshita Kohei, Watanuki Shintaro, Kobayashi Hiroshi, Kanai-Sudo Hikari, Naito Yoshiko, Hayakawa Noriyo, Matsuura Tomomi, Hishiki Takako, Matsui Minoru, Tsutsui Masato, Suematsu Makoto, Takubo Keiyo
Department of Stem Cell Biology, National Institute of Global Health and Medicine, Japan Institute for Health Security, Tokyo, Japan.
Multiomics Platform, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Nat Commun. 2025 Jul 1;16(1):5475. doi: 10.1038/s41467-025-60515-9.
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.
骨髓（BM）招募移植的造血干细胞和祖细胞（HSPCs）的能力随年龄增长而下降，限制了基于HSPC的医学应用潜力。通过体内成像和操作结合综合代谢组学分析，我们发现，随着年龄增长，非神经源性乙酰胆碱的降解会破坏局部Chrm5-eNOS-一氧化氮信号传导，减少动脉扩张，降低骨髓血流量和窦壁剪切应力。因此，衰老的骨髓微环境会损害移植的HSPCs的跨内皮迁移，其骨髓归巢效率降低，这是由Piezo1激活减少介导的。值得注意的是，Piezo1的药理学激活可提高老年受体的HSPC归巢效率和移植后存活率。这些发现表明，局部动脉与年龄相关的失调会通过降低剪切应力导致HSPC向骨髓的归巢受损。调节这些机制可能会提高老年患者临床移植的疗效和安全性。
