Decreased non-neurogenic acetylcholine in bone marrow triggers age-related defective stem/progenitor cell homing
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, degrad...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60515-9 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Takayuki Morikawa |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a4352fc011594d57a584cc08fcb674d0 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a4352fc011594d57a584cc08fcb674d02025-08-20T03:37:37ZengNature PortfolioNature Communications2041-17232025-07-0116111710.1038/s41467-025-60515-9Decreased non-neurogenic acetylcholine in bone marrow triggers age-related defective stem/progenitor cell homingTakayuki Morikawa0Shinya Fujita1Yuki Sugiura2Shinpei Tamaki3Miho Haraguchi4Kohei Shiroshita5Shintaro Watanuki6Hiroshi Kobayashi7Hikari Kanai-Sudo8Yoshiko Naito9Noriyo Hayakawa10Tomomi Matsuura11Takako Hishiki12Minoru Matsui13Masato Tsutsui14Makoto Suematsu15Keiyo Takubo16Department of Stem Cell Biology, National Institute of Global Health and Medicine, Japan Institute for Health SecurityDepartment of Stem Cell Biology, National Institute of Global Health and Medicine, Japan Institute for Health SecurityMultiomics Platform, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of MedicineDepartment of Stem Cell Biology, National Institute of Global Health and Medicine, Japan Institute for Health SecurityDepartment of Stem Cell Biology, National Institute of Global Health and Medicine, Japan Institute for Health SecurityDepartment of Stem Cell Biology, National Institute of Global Health and Medicine, Japan Institute for Health SecurityDepartment of Stem Cell Biology, National Institute of Global Health and Medicine, Japan Institute for Health SecurityDepartment of Stem Cell Biology, National Institute of Global Health and Medicine, Japan Institute for Health SecurityDepartment of Stem Cell Biology, National Institute of Global Health and Medicine, Japan Institute for Health SecurityClinical Translational Research Center, Keio University HospitalCentral Institute for Experimental Medicine and Life ScienceClinical Translational Research Center, Keio University HospitalDepartment of Health Chemistry, Showa Pharmaceutical University, MachidaYokokawa Ladies ClinicDepartment of Pharmacology, Graduate School of Medicine, University of the RyukyusWPI-Bio2Q Research Center, Keio UniversityDepartment of Stem Cell Biology, National Institute of Global Health and Medicine, Japan Institute for Health SecurityAbstract 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.https://doi.org/10.1038/s41467-025-60515-9 |
| spellingShingle | 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 Decreased non-neurogenic acetylcholine in bone marrow triggers age-related defective stem/progenitor cell homing Nature Communications |
| title | Decreased non-neurogenic acetylcholine in bone marrow triggers age-related defective stem/progenitor cell homing |
| title_full | Decreased non-neurogenic acetylcholine in bone marrow triggers age-related defective stem/progenitor cell homing |
| title_fullStr | Decreased non-neurogenic acetylcholine in bone marrow triggers age-related defective stem/progenitor cell homing |
| title_full_unstemmed | Decreased non-neurogenic acetylcholine in bone marrow triggers age-related defective stem/progenitor cell homing |
| title_short | Decreased non-neurogenic acetylcholine in bone marrow triggers age-related defective stem/progenitor cell homing |
| title_sort | decreased non neurogenic acetylcholine in bone marrow triggers age related defective stem progenitor cell homing |
| url | https://doi.org/10.1038/s41467-025-60515-9 |
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