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Haematopoietic stem cells in perisinusoidal niches are protected from ageing
Open accessAbstract
With ageing, intrinsic haematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to diseases. However, whether ageing also affects the HSC niche, and thereby impairs its capacity to support HSC function, is still widely debated. Here, by using in-vivo long-term label-retention assays we demonstrate that aged label-retaining HSCs, which are, in old mice, the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches. Furthermore, we demonstrate that sinusoidal niches are uniquely preserved in shape, morphology and number on ageing. Finally, we show that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches in the long term, which is linked to the lack of recovery of endothelial Jag2 at sinusoids. Overall, our data characterize the functional alterations of the aged HSC niche and unveil that perisinusoidal niches are uniquely preserved and thereby protect HSCs from ageing.
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“Likewise, in bone marrow from old mice, a pool of quiescent HSCs located close to sinusoids (FIG. 1b) may be protected from some ageing effects38.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [38]
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“A lack of Jag2 in the perisinusoidal endothelial niche accelerated aging of hematopoietic stem cells (Saçma et al., 2019).”
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Recent advances in “sickle and niche” research - Tribute to Dr. Paul S Frenette -
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Self-citationRole of macrophages and phagocytes in orchestrating normal and pathologic hematopoietic niches
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Human hematopoietic microenvironments
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“Because of the evidence regarding the influence of aging on the HSPC microenvironment [14,56], we investigated whether it was possible to find any correlations between aging and HSPC localization; which we were not able to find.”
BackgroundTargeting RhoA nuclear mechanoactivity rejuvenates aged hematopoietic stem cells
Mejía-Ramírez, E., Picazo, P. I., Walter, B., Montserrat‐Vazquez, S., Affuso, F., Wieser, S., Pezzano, F., Reymond, L., Castillo‐Robles, J., Matteini, F., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-01014-w · Cited by 15
Self-citationPlasma cell derived mtDAMPs activate macrophage STING pathway which promotes myeloma progression.
Jibril, A. S., Hellmich, C., Wojtowicz, E. E., Hampton, K., Maynard, R. S., Silva, R. D., Fowler-Shorten, D. J., Mistry, J. J., Moore, J. A., Bowles, K. M., et al. (2023) · Blood · doi:10.1182/blood.2022018711 · Cited by 13
Xinyi, Y., Vladimirovich, R. I., Beeraka, N. M., Satyavathi, A., Kamble, D., Nikolenko, V. N., Lakshmi, A. N., Basappa, B., Padmanabha Reddy, Y., Fan, R., et al. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-04008-4 · Cited by 11
“As the age increases, the alterations occur in the vasculature, marked by the decline in CD31 high Endomu-cin −/low arterioles [147, 151, 208].”
BackgroundWatt, S. M. (2022) · PubMed Central · doi:10.12336/biomatertransl.2022.01.005 · Cited by 11
Proliferation: Driver of HSC aging phenotypes?
Yanai, H., & Beerman, I. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111331 · Cited by 9
Xiao, M., Hong, S., Peng, P., Cai, S., Huang, Y., Liang, J., Bai, X., Bao, Q., Li, W., Cheng, G., et al. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155978 · Cited by 9
The aging hematopoietic stem cell niche: a mini review
Gao, X., Zhang, J., & Tamplin, O. J. (2025) · Frontiers in Hematology · doi:10.3389/frhem.2025.1525132 · Cited by 11
“Some have observed that endosteal ECs, like arterioles and TZVs, are reduced during aging, but overall EC volume and area occupancy are unchanged, leading to the conclusion that BM sinusoids are preserved upon aging (15).”
Yang, F., Nourse, C., Helgason, G. V., & Kirschner, K. (2023) · HemaSphere · doi:10.1097/hs9.0000000000000895 · Cited by 12
“59 61 However, the expression of the cell surface receptor LepR increases in human MSCs with increased age.”
El‐naseery, N. I., Elewa, Y. H. A., El-behery, E., & Dessouky, A. A. (2023) · Annals of Anatomy - Anatomischer Anzeiger · doi:10.1016/j.aanat.2023.152131 · Cited by 9
Hematopoietic Stem Cells and Their Bone Marrow Niches
Pinho, S., & Zhao, M. L. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-981-99-7471-9_2 · Cited by 9
Aberrant engagement of P-selectin drives hematopoietic stem cell aging in mice
Yang, D., Skinder, N., Kao, Y.-R., Chen, J., Thiruthuvanathan, V. J., Svendsen, A. F., Zhang, C., Dethmers-Ausema, B., Weersing, E., Maryanovich, M., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-00880-8 · Cited by 11
The role of the stem cell epigenome in normal aging and rejuvenative therapy
Jayarajan, J., & Milsom, M. D. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa167 · Cited by 8
Self-citationSaçma, M., Matteini, F., Mulaw, M. A., Hageb, A., Bogeska, R., Sakk, V., Vollmer, A., Marka, G., Soller, K., Milsom, M. D., et al. (2022) · STAR Protocols · doi:10.1016/j.xpro.2022.101483 · Cited by 8
Self-citation3D In Vitro Models of the Bone Marrow Niche
Scala, P., Serio, B., & Giudice, V. (2025) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.5c01421 · Cited by 7
Skinder, N., Fernández, I. S., Dethmers-Ausema, A., Weersing, E., & de Haan, G. (2023) · Blood Advances · doi:10.1182/bloodadvances.2023011585 · Cited by 8
Current Trends on Hemopoietic Stem Cells
Okeke, C., Silas, U., Okeke, C., & Chikwendu, C. (2020) · Current Stem Cell Research & Therapy · doi:10.2174/1574888x15999200729162021 · Cited by 6
Omatsu, Y., Higaki, K., & Nagasawa, T. (2021) · Current topics in microbiology and immunology · doi:10.1007/978-3-030-86016-5_2 · Cited by 6
Dissecting dormancy and quiescence in hematopoietic stem cells
Ibneeva, L., & Grinenko, T. (2024) · Frontiers in Hematology · doi:10.3389/frhem.2024.1401713 · Cited by 7
Meeting Report: Aging Research and Drug Discovery
Meron, E., Thaysen, M., Angeli, S., Antebi, A., Barzilai, N., Baur, J. A., Bekker‐Jensen, S., Birkisdóttir, M. B., Bischof, E. Y., Bruening, J., et al. (2022) · Aging · doi:10.18632/aging.203859 · Cited by 7
“Only functional aged HSCs are located at sinusoids, thus, the sinusoids are critical for their support, which is especially important to consider when treating with chemotherapy as it disrupts the sinusoids [29].”
BackgroundSelf-citationBone marrow niches in myelodysplastic syndromes
Tosato, G., Feng, J., Ohnuki, H., & Sim, M. (2021) · Journal of Cancer Metastasis and Treatment · doi:10.20517/2394-4722.2021.120 · Cited by 4
“The most quiescent HSC in aged mice reside in sinusoidal niches, which appear critical to protecting HSC from aging; endothelial derived Jag2 may be an essential sinusoidal niche factor[23].”
BackgroundMilsom, M. D., & Essers, M. A. G. (2023) · Cells and Development · doi:10.1016/j.cdev.2023.203844 · Cited by 4
Self-citationResilient anatomy and local microplasticity of naïve and stress hematopoiesisPreprint
Wu, Q., Zhang, J., Johnson, C. B., Slaughter, A., Weinhaus, B., McKnight, M., Sherman, B. E., Shao, T., Song, B., Filippi, M., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.23.492315 · Cited by 4
Endosteal stem cells at the bone‐blood interface: A double‐edged sword for rapid bone formation
Matsushita, Y., Liu, J., Chu, A. K. Y., Ono, W., Welch, J. D., & Ono, N. (2023) · BioEssays · doi:10.1002/bies.202300173 · Cited by 3
Functional Specialization of the Calvarial Bone Marrow
Koh, B. I., & Adams, R. H. (2025) · Physiology · doi:10.1152/physiol.00028.2025 · Cited by 3
Tissot, F. S., González-Antón, S., & Celso, C. L. (2023) · Methods in molecular biology · doi:10.1007/978-1-0716-3589-6_17 · Cited by 3
Stress-protecting harbors for hematopoietic stem cells
Yang, Z., Dong, R., Mao, X., He, X., & Li, L. (2023) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2023.102284 · Cited by 5
The role of genetic/epigenetic factors and microenvironment in hematopoietic stem cell ageing
Niazi, V., Parseh, B., & Ghafouri‐Fard, S. (2025) · Biogerontology · doi:10.1007/s10522-025-10218-x · Cited by 3
“Thus, while aged HSCs niche underwent changes, perisinusoidal niche was exceptionally conserved and protect HSCs from ageing (Saçma et al. 2019).”
Abbasizadeh, N., Burns, C. S., Verrinder, R., Ghazali, F., Seyedhassantehrani, N., & Spencer, J. A. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1441381 · Cited by 2
Allgöwer, C., Mulaw, M. A., Nagai, J., Wiedenmann, S., Ringel, E. A., Ferrara, B., Piemonti, L., Maulana, T. I., Ferreira, L. T., Flinders, A., et al. (2026) · Molecular Cancer · doi:10.1186/s12943-025-02541-1 · Cited by 4
“Details on model setup have been previously described [63].”
InfluentialSelf-citationShi, C., Zhang, K., Zhao, Z., Wang, Y., Xu, H., & Wei, W. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1080563 · Cited by 2
“Aging affects the activity of stem cells and weakens their ability (Saçma et al., 2019).”
BackgroundHo, A. D., & Tanaka, M. (2024) · Experimental Hematology · doi:10.1016/j.exphem.2024.104686 · Cited by 2
Aging, Causes, and Rejuvenation of Hematopoietic Stem Cells
Chen, Z., Ju, Z., & Sun, Y. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-981-99-7471-9_12 · Cited by 1
Bueno, V. (2024) · Springer eBooks · doi:10.1007/978-3-031-55022-5_7 · Cited by 1
NO-immune privilege for hematopoietic stem cells
Chédeville, A. L., & Méndez‐Ferrer, S. (2025) · Cell Research · doi:10.1038/s41422-025-01087-7 · Cited by 1
Self-citation
Metadata
- Authors
- Saçma, M., Pospiech, J., Bogeska, R., de Back, W., Mallm, J.-P., Sakk, V., Soller, K., Marka, G., Vollmer, A., Karns, R., Cabezas-Wallscheid, N., Trumpp, A., Méndez-Ferrer, S., Milsom, M. D., Mulaw, M. A., Geiger, H., & Florian, M. C.
- Affiliations
- Universität Ulm (DE)
- German Cancer Research Center (DE)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Florian, Maria Carolina
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2019-11
- Volume
- 21
- Issue
- 11
- Pages
- 1309-1320
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2986117925
- Cited by
- 133
- References
- 81
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 18 · 2023: 23 · 2022: 19 · 2021: 26 · 2020: 21 · 2019: 2
- FWCI
- 12.10
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Deutsche Forschungsgemeinschaft (FL 921/1-1, FOR2674, SFB1074)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Health Sciences › Medicine › Hematology › Blood disorders and treatments
- Keywords
- hematopoietic stem cells, aging, HSC quiescence, myeloablative chemotherapy, bone marrow microenvironment
- MeSH terms
- Jagged-2 Protein, Aging, Animals, Bone Marrow, Capillaries, Cell Differentiation, Cell Division, Doxycycline, Fluorouracil, Gene Expression Regulation, Hematopoietic Stem Cells, Histones, Homeostasis, Mice, Inbred C57BL, Mice, Transgenic, Cell Polarity, Genes, Reporter, Hematopoietic Stem Cell Transplantation, Myeloablative Agonists, Green Fluorescent Proteins, Mice, Stem Cell Niche, Cell Tracking
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