Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells
Open accessAbstract
Hematopoietic stem cell (HSC) populations change with aging, but the extent to which this is caused by qualitative versus quantitative alterations in HSC subtypes is unclear. Using clonal assays, in this study we show that the aging HSC compartment undergoes both quantitative and qualitative changes. We observed a variable increase of HSC pool size with age, accompanied by the accumulation of predominantly myeloid-biased HSCs that regenerate substantially fewer mature progeny than young myeloid-biased HSCs and exhibit reduced self-renewal activity as measured by long-term secondary transplantation. Old HSCs had a twofold reduction in marrow-homing efficiency and a similar decrease in functional frequency as measured using long-term transplantation assays. Similarly, old HSCs had a twofold reduced seeding efficiency and a significantly delayed proliferative response compared with young HSCs in long-term stromal cell co-cultures but were indistinguishable in suspension cultures. We show that these functional defects are characteristics of most or all old HSCs and are not indicative of a nonfunctional subset of cells that express HSC markers. Furthermore, we demonstrate that cells with functional properties of old HSCs can be generated directly from young HSCs by extended serial transplantation, which is consistent with the possibility that they arise through a process of cellular aging.
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Myeloid-biased stem cells in old mice are less robust than those in young mice.
“Despite the increase in their number, myeloid-biased stem cells are not as robust as their young counterparts (24)”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [24]
Aged HSCs transplanted into young mice are functionally worse than young HSCs.
“That aged HSC are functionally impaired compared with their young counterparts upon transplantation in young mice”
From Aging of hematopoietic stem cells (2018) · cites this paper as [10]
The functional heterogeneity of the HSC population rises with age.
“the functional heterogeneity of the HSC population increases with age.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [10]
Aged mice have an overall larger HSC pool.
“in aged mice that display an overall increase in HSC pool size”
From Aging of hematopoietic stem cells (2018) · cites this paper as [10]
Individual HSCs in aged mice behave very differently from one another.
“individual HSCs behave very differently.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [10]
Mice whose blood cell production comes from even a single stem cell are not necessarily prone to leukemia.
“mice in which blood cell production is derived from even a single stem cell, are not necessarily prone to develop leukemia.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [10]
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Cites
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“These characteristics of HSC aging can, in part, be experimentally recapitulated by increasing the proliferative history of HSCs or stressing them with multiple injections of myeloablative chemotherapeutic regimens (57), or by conducting serial transplantations (“experimental aging”) (34, 35).”
BackgroundGrover, A., Sanjuán-Pla, A., Thongjuea, S., Carrelha, J., Giustacchini, A., Gambardella, A. R., Macaulay, I. C., Mancini, E., Luis, T. C., Mead, A. J., et al. (2016) · Nature Communications · doi:10.1038/ncomms11075 · Cited by 339 · see citing works
“Genes (11,910) were selected for PCA analysis based on coefficient of variation (CVZ1) and mean of expression values across all cells (log2(CPM)40).”
MethodBenz, C., Copley, M. R., Kent, D. G., Wöhrer, S., Cortés, A., Aghaeepour, N., Ma, E., Mader, H., Rowe, K. M., Day, C. W., et al. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.02.007 · Cited by 322 · see citing works
“The observation of dominant a-HSCs in old mice confirms similar recent reports of an alteration in the composition of the HSC compartment during aging (Beerman et al., 2010; Cho et al., 2008; Dykstra et al., 2011) and is relevant to the question of the mechanisms responsible for the well-documented age-associated decl…”
ResultWhen stem cells grow old: phenotypes and mechanisms of stem cell aging
Schultz, M. B., & Sinclair, D. A. (2016) · Development · doi:10.1242/dev.130633 · Cited by 331 · see citing works
“Only when function was measured on a per-cell basis were old immunophenotypic HSCs shown to have a greatly reduced ability to engraft and properly differentiate in new hosts (Dykstra et al., 2011; Liang et al., 2005; Morrison et al., 1996).”
BackgroundHo, Y.-H., del Toro, R., Rivera-Torres, J., Rak, J., Korn, C., García-García, A., Macías, D., González-Gómez, C., del Monte, A., Wittner, M., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2019.06.007 · Cited by 315 · see citing works
“Although HSC aging was initially regarded as solely derived from intrinsic changes in HSCs (Chambers et al., 2007; Dykstra et al., 2011; Florian et al., 2013; Rossi et al., 2007), several alterations in the BM microenvironment or in its interaction with HSCs have been proposed to promote hematopoietic aging (Ergen et…”
BackgroundInduction of myelodysplasia by myeloid-derived suppressor cells
Chen, X., Eksioglu, E. A., Zhou, J., Zhang, L., Djeu, J., Fortenbery, N., Epling-Burnette, P., Van Bijnen, S., Dolstra, H., Cannon, J., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67580 · Cited by 316 · see citing works
“…indicate that TRAF6 is essential for survival and proliferation of MDS HSPC (11) and sustained TLR activation skews their commitment toward the myeloid lineage while suppressing osteoblast differentiation (12, 13), analogous to the senescence-dependent changes observed with normal aging (14).”
Hematopoietic progenitor cells as integrative hubs for adaptation to and fine-tuning of inflammation
Chavakis, T., Mitroulis, I., & Hajishengallis, G. (2019) · Nature Immunology · doi:10.1038/s41590-019-0402-5 · Cited by 318 · see citing works
Hematopoietic stem cells count and remember self-renewal divisions
Bernitz, J. M., Kim, H. S., MacArthur, B., Sieburg, H., & Moore, K. (2016) · Cell · doi:10.1016/j.cell.2016.10.022 · Cited by 285 · see citing works
“While the HSC compartment expands dramatically with age (Beerman et al., 2010; Dykstra et al., 2011; Rossi et al., 2005; Sudo et al., 2000), functional LTHSC numbers within aging BM expand but to a lesser extent (Cho et al., 2008; Morrison et al., 1996; Sudo et al., 2000).”
InfluentialGuan, J., Simon, A. K., Prescott, M., Menéndez, J. A., Liu, F., Wang, F., Wang, C., Wolvetang, E. J., Vázquez‐Martín, A., & Zhang, J. (2013) · Autophagy · doi:10.4161/auto.24132 · Cited by 285 · see citing works
“HSCs from aged mice show a reduced repopulating activity per cell, attenuated self-renewal and homing abilities, myeloid skewing of differentiation, and an increased level of stress-induced apoptosis.(74) This phenotype is largely reminiscent of the one found in HSCs from mice deficient for ATG7 or RB1CC1/FIP200.”
BackgroundAging, inflammation, immunity and periodontal disease
Ebersole, J. L., Graves, C. L., González, O. A., Dawson, D. R., Morford, L. A., Emecen‐Huja, P., Hartsfield, J. K., Huja, S. S., Pandruvada, S. N. M., & Wallet, S. M. (2016) · Periodontology 2000 · doi:10.1111/prd.12135 · Cited by 308 · see citing works
Chaperone-mediated autophagy sustains haematopoietic stem-cell function
Dong, S., Wang, Q., Kao, Y.-R., Diaz, A., Tasset, I., Kaushik, S., Thiruthuvanathan, V., Zintiridou, A., Nieves, E., Dzieciatkowska, M., et al. (2021) · Nature · doi:10.1038/s41586-020-03129-z · Cited by 275 · see citing works
The stem cell niche in regenerative medicine.
Wagers, A. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2012.02.018 · Cited by 281 · see citing works
“Likewise, high throughput chemical screening using purified human HSCs has identified soluble signals, such as inhibition of ligand-induced signaling by the aryl hydrocarbon receptor (AhR), that can promote in vitro expansion of umbilical cord and mobilized peripheral blood-derived human HSCs (Boitano et al., 2010; M.…”
BackgroundInfluentialMacrophages in age-related chronic inflammatory diseases
Oishi, Y., & Manabe, I. (2016) · npj Aging and Mechanisms of Disease · doi:10.1038/npjamd.2016.18 · Cited by 262 · see citing works
“Despite the skewing of aged HSCs toward myelopoiesis, however, the basal inflammation seen in older individuals is not associated with increased numbers of myeloid cells, presumably reflecting multiple functional defects in the homing and proliferative responses of aged HSCs.(1,15) Immunosenescence leads not only to i…”
BackgroundImmune aging, dysmetabolism, and inflammation in neurological diseases
Deleidi, M., Jäggle, M., & Rubino, G. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00172 · Cited by 260 · see citing works
“Diseases (DZNE), Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller.”
BackgroundInfluentialThe Human Cell Atlas bone marrow single-cell interactive web portal
Hay, S. B., Ferchen, K., Chetal, K., Grimes, H. L., & Salomonis, N. (2018) · Experimental Hematology · doi:10.1016/j.exphem.2018.09.004 · Cited by 256 · see citing works
Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential
Luchsinger, L. L., de Almeida, M. J., Corrigan, D., Mumau, M. D., & Snoeck, H. (2016) · Nature · doi:10.1038/nature16500 · Cited by 248 · see citing works
Roles of JAK2 in Aging, Inflammation, Hematopoiesis and Malignant Transformation
Perner, F., Perner, C., Ernst, T., & Heidel, F. H. (2019) · Cells · doi:10.3390/cells8080854 · Cited by 247 · see citing works
“As the hematopoietic system ages, somatic mutations lead to a decline in the HSC function and skewing towards the myeloid compartment [1,2].”
BackgroundThe hematopoietic stem cell niche: from embryo to adult
Gao, X., Xu, C., Asada, N., & Frenette, P. S. (2018) · Development · doi:10.1242/dev.139691 · Cited by 247 · see citing works
“Aged HSCs are more proliferative and their numbers increase in the aged bone marrow (de Haan et al., 1997; Dykstra et al., 2011; Morrison et al., 1996; Rossi et al., 2005).”
BackgroundKlauke, K., Radulović, V., Broekhuis, M., Weersing, E., Zwart, E., Olthof, S., Ritsema, M., Bruggeman, S., Wu, X., Helin, K., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2701 · Cited by 237 · see citing works
Self-citationLineage-Biased Hematopoietic Stem Cells Are Regulated by Distinct Niches
Pinho, S., Marchand, T., Yang, E. M., Wei, Q., Nerlov, C., & Frenette, P. S. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.01.016 · Cited by 235 · see citing works
“…et al., 2002; Sanjuan-Pla et al., 2013; Sieburg et al., 2006), whereas myeloid-biased HSCs become dominant with age (Cho et al., 2008; Dykstra et al., 2011; Grover et al., 2016) with declined long-term self-renewal functions, possibly contributing to the development of hematologic…”
BackgroundEpigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells
Yu, V. W. C., Yusuf, R. Z., Oki, T., Wu, J. W., Sáez, B., Wang, X., Cook, C., Baryawno, N., Ziller, M. J., Lee, E., et al. (2017) · Cell · doi:10.1016/j.cell.2017.02.010 · Cited by 234 · see citing works
Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity
Ross, J., Myers, L. M., Noh, J. J., Collins, M. M., Carmody, A., Messer, R. J., Dhuey, E., Hasenkrug, K. J., & Weissman, I. L. (2024) · Nature · doi:10.1038/s41586-024-07238-x · Cited by 239 · see citing works
Targeting immune dysfunction in aging
Borgoni, S., Kudryashova, K. S., Burka, K., & de Magalhães, J. P. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101410 · Cited by 227 · see citing works
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Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging
Young, K., Eudy, E., Bell, R., Loberg, M. A., Stearns, T., Sharma, D., Velten, L., Haas, S., Filippi, M.-D., & Trowbridge, J. J. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.03.017 · Cited by 216 · see citing works
Impact of genomic damage and ageing on stem cell function
Behrens, A., van Deursen, J. M., Rudolph, K. L., & Schumacher, B. (2014) · Nature Cell Biology · doi:10.1038/ncb2928 · Cited by 207 · see citing works
Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment
Yamamoto, R., Wilkinson, A. C., Ooehara, J., Lan, X., Lai, C.-Y., Nakauchi, Y., Pritchard, J. K., & Nakauchi, H. (2018) · Cell Stem Cell · doi:10.1016/j.stem.2018.03.013 · Cited by 202 · see citing works
“, 2011), myeloid-biased differentiation (Dykstra et al., 2011; Sudo et al., 2000), P-biased differentiation (Grover et al.”
InfluentialThe multifaceted role of autophagy in cancer and the microenvironment
Folkerts, H., Hilgendorf, S., Vellenga, E., Bremer, E., & Wiersma, V. R. (2018) · Medicinal Research Reviews · doi:10.1002/med.21531 · Cited by 201 · see citing works
Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells
Yu, V. W. C., Yusuf, R. Z., Oki, T., Wu, J. W., Sáez, B., Wang, X., Cook, C., Baryawno, N., Ziller, M. J., Lee, E., et al. (2016) · Cell · doi:10.1016/j.cell.2016.10.045 · Cited by 200 · see citing works
“…November 17, 2016 ª 2016 Elsevier Inc. to exhibit bias toward myeloid, lymphoid, or megakaryocytic lineage upon transplantation of single cells (Dykstra et al., 2007, 2011; Morita et al., 2010), on ex vivo barcoding and transplantation of populations (Aiuti et al., 2013; Gerrits et al.,…”
BackgroundHeterogeneous Responses of Hematopoietic Stem Cells to Inflammatory Stimuli Are Altered with Age
Mann, M., Mehta, A., de Boer, C. G., Kowalczyk, M. S., Lee, K., Haldeman, P., Rogel, N., Knecht, A. R., Farouq, D., Regev, A., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.11.056 · Cited by 188 · see citing works
Hematopoiesis and Cardiovascular Disease
Poller, W. C., Nahrendorf, M., & Świrski, F. K. (2020) · Circulation Research · doi:10.1161/circresaha.120.315895 · Cited by 183 · see citing works
Verovskaya, E. V., Broekhuis, M., Zwart, E., Ritsema, M., van Os, R. P., de Haan, G., & Bystrykh, L. V. (2013) · Blood · doi:10.1182/blood-2013-01-481135 · Cited by 175 · see citing works
“Studies of unmanipulated old and young HSCs have indicated an ;twofold reduced functional activity of old cells.(13) To compensate for the expected decrease of functional activity in old HSCs, we initiated the experiment with LSK48(2)150(1) cells from young and old mice cotransplanted in a 1:2 ratio (Figure 6A).”
BackgroundMethodResultInfluentialSelf-citationMyeloproliferative neoplasm stem cells.
Mead, A., & Mullally, A. (2017) · Blood · doi:10.1182/blood-2016-10-696005 · Cited by 167 · see citing works
“Given the increased prevalence of CHIP in older individuals, it is interesting to note that aging has significant effects on HSC heterogeneity, including an increase in myeloid-biased differentiation, a decreased output of differentiated cells, and a reduced capacity for self-renewal in longterm secondary transplantat…”
BackgroundMitochondrial Potentiation Ameliorates Age-Related Heterogeneity in Hematopoietic Stem Cell Function
Mansell, E., Sigurðsson, V., Deltcheva, E. M., Brown, J., James, C. T., Miharada, K., Soneji, S., Larsson, J. T., & Enver, T. (2020) · Cell stem cell · doi:10.1016/j.stem.2020.09.018 · Cited by 176 · see citing works
“Upon aging of the hematopoietic system, the phenotypic HSC pool expands but collectively displays reduced repopulation capacity, increased clonality, myeloid-biased blood output, and lymphoid and erythroid deficiency (Sudo et al., 2000; Liang et al., 2005; Norddahl et al., 2011; Dykstra et al., 2011; Grover et al., 20…”
BackgroundHematopoietic Stem Cell Heterogeneity Takes Center Stage
Copley, M. R., Beer, P. A., & Eaves, C. J. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.05.006 · Cited by 174 · see citing works
“Likewise, the initial pattern of differentiation by which they are defined is frequently expressed by their clonally generated daughter HSCs when these are transplanted into secondary mice (Benz Cell et al., 2012; Dykstra et al., 2007, 2011; MüllerSieburg et al., 2002, 2012).”
BackgroundInfluentialAging, Clonality, and Rejuvenation of Hematopoietic Stem Cells
Akunuru, S., & Geiger, H. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.06.003 · Cited by 172 · see citing works
“This feature of aged HSCs is demonstrated to be a cellautonomous function [3,31].”
BackgroundIL-1 mediates microbiome-induced inflammaging of hematopoietic stem cells in mice
Kovtonyuk, L. V., Caiado, F., Garcia-Martin, S., Manz, E.-M., Helbling, P., Takizawa, H., Boettcher, S., Al-Shahrour, F., Nombela-Arrieta, C., Slack, E., et al. (2022) · Blood · doi:10.1182/blood.2021011570 · Cited by 166 · see citing works
B cell maintenance and function in aging
Kogut, I., Scholz, J. L., Cancro, M. P., & Cambier, J. C. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.04.004 · Cited by 166 · see citing works
Horiguchi, H., Loftus, T. J., Hawkins, R. B., Raymond, S. L., Stortz, J. A., Hollen, M. K., Weiss, B. P., Miller, E. S., Bihorac, A., Larson, S. D., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00595 · Cited by 164 · see citing works
“They have a lower functional frequency, a delayed proliferative response, and a reduced efficiency for short-term BM homing, and they produce smaller clones of mature cells and have a reduced long-term selfrenewal activity (210, 211).”
BackgroundStem cell heterogeneity: implications for aging and regenerative medicine
Müller‐Sieburg, C. E., Sieburg, H. B., Bernitz, J. M., & Cattarossi, G. (2012) · Blood · doi:10.1182/blood-2011-12-376749 · Cited by 164 · see citing works
“However, in a carefully executed study, Dykstra and colleagues recently examined a very large number of CD150+ HSC clones and reported that CD150+ cells from aged mice have less self-renewal capacity and home less efficiently to BM than CD150+ cells isolated from young animals.(55) This deficit can be attributed large…”
InfluentialAging disrupts circadian gene regulation and function in macrophages
Blacher, E., Tsai, C. A., Litichevskiy, L., Shipony, Z., Iweka, C. A., Schneider, K. M., Chuluun, B., Heller, H. C., Menon, V., Thaiss, C. A., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-01083-0 · Cited by 164 · see citing works
Zeng, X., Li, X., Li, X., Wei, C., Shi, C., Hu, K., Kong, D., Luo, Q., Xu, Y., Shan, W., et al. (2023) · Blood · doi:10.1182/blood.2022017514 · Cited by 157 · see citing works
Aging alters the epigenetic asymmetry of HSC division
Florian, M. C., Klose, M., Saçma, M., Jablanovic, J., Knudson, L. A., Nattamai, K., Marka, G., Vollmer, A., Soller, K., Sakk, V., et al. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2003389 · Cited by 154 · see citing works
Rimmelé, P., Bigarella, C. L., Liang, R. H.-S., Izac, B., Dieguez‐Gonzalez, R., Barbet, G., Donovan, M. J., Brugnara, C., Blander, J. M., Sinclair, D. A., et al. (2014) · Stem Cell Reports · doi:10.1016/j.stemcr.2014.04.015 · Cited by 154 · see citing works
“3 j 44–59 j July 8, 2014 j a2014 The Authors prominent modifications of HSC properties with age is their biased differentiation toward myeloid lineage at the expense of their lymphoid potential (Challen et al., 2010; Dykstra et al., 2011; Rossi et al., 2005).”
BackgroundFunctional dysregulation of stem cells during aging: a focus on skeletal muscle stem cells
García‐Prat, L., Sousa‐Victor, P., & Muñoz‐Cánoves, P. (2013) · The FEBS Journal · doi:10.1111/febs.12221 · Cited by 152 · see citing works
Microenvironmental contributions to hematopoietic stem cell aging
Ho, Y., & Méndez‐Ferrer, S. (2019) · Haematologica · doi:10.3324/haematol.2018.211334 · Cited by 149 · see citing works
Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors
Henry, C. J., Casás-Selves, M., Kim, J., Zaberezhnyy, V., Aghili, L., Daniel, A. E., Jimenez, L., Azam, T., McNamee, E. N., Clambey, E. T., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci83024 · Cited by 148 · see citing works
Nilsson, A. R., Soneji, S., Adolfsson, S., Bryder, D., & Pronk, C. J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0158369 · Cited by 149 · see citing works
“In several reports, aged murine HSCs have been characterized by an increased myeloid-to-lymphoid output, often referred to as a myeloid bias (My-bi), although also their myeloid cell forming ability is decreased on a per cell basis when compared to younger HSCs [14, 18].”
ResultJakobsen, N. A., Turkalj, S., Zeng, A. G. X., Stoilova, B., Metzner, M., Rahmig, S., Nagree, M. S., Shah, S., Moore, R., Usukhbayar, B., et al. (2024) · Cell Stem Cell · doi:10.1016/j.stem.2024.05.010 · Cited by 130 · see citing works
Neutrophils in aging and aging‐related pathologies
Avondt, K. V., Strecker, J., Tulotta, C., Minnerup, J., Schulz, C., & Soehnlein, O. (2022) · Immunological Reviews · doi:10.1111/imr.13153 · Cited by 146 · see citing works
A comprehensive transcriptome signature of murine hematopoietic stem cell aging
Flohr Svendsen, A., Yang, D., Kim, K., Lazare, S., Skinder, N., Zwart, E., Mura-Meszaros, A., Ausema, A., von Eyss, B., de Haan, G., et al. (2021) · Blood · doi:10.1182/blood.2020009729 · Cited by 138 · see citing works
Plasma cells are obligate effectors of enhanced myelopoiesis in aging bone marrow
Pioli, P. D., Casero, D., Montecino-Rodriguez, E., Morrison, S. L., & Dorshkind, K. (2019) · Immunity · doi:10.1016/j.immuni.2019.06.006 · Cited by 131 · see citing works
“, 2005) that includes a significant increase in the frequency and number of hematopoietic stem cells (HSCs) (Dykstra and de Haan, 2008; Geiger and Van Zant, 2002), common myeloid progenitors (CMPs), granulocytemacrophage progenitors (GMPs) and mature myeloid cells (Dykstra et al., 2011; Tang et al., 2013).”
BackgroundWill, B., Vogler, T. O., Narayanagari, S., Bartholdy, B., Todorova, T. I., da Silva Ferreira, M., Chen, J., Yu, Y., Mayer, J., Barreyro, L., et al. (2015) · Nature Medicine · doi:10.1038/nm.3936 · Cited by 127 · see citing works
Age-associated changes in human hematopoietic stem cells
Pang, W. W., Schrier, S. L., & Weissman, I. L. (2016) · Seminars in Hematology · doi:10.1053/j.seminhematol.2016.10.004 · Cited by 123 · see citing works
Djeghloul, D., Kuranda, K., Kuzniak, I., Barbieri, D., Naguibneva, I., Choisy, C., Bories, J.-C., Dosquet, C., Pla, M., Vanneaux, V., et al. (2016) · Stem Cell Reports · doi:10.1016/j.stemcr.2016.05.007 · Cited by 122 · see citing works
“Studies in both humans and mice have shown that HSC are not constant throughout life (Chambers et al., 2007; Dykstra et al., 2011; Flach et al., 2014; Kuranda et al., 2011; Lescale et al., 2010; Pang et al., 2011; Rossi et al., 2005).”
BackgroundValletta, S., Thomas, A., Meng, Y., Ren, X., Drissen, R., Sengül, H., Di Genua, C., & Nerlov, C. (2020) · Nature Communications · doi:10.1038/s41467-020-17942-7 · Cited by 122 · see citing works
Mechanisms and rejuvenation strategies for aged hematopoietic stem cells
Li, X., Zeng, X., Xu, Y., Wang, B., Zhao, Y., Lai, X., Qian, P., & Huang, H. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00864-8 · Cited by 118 · see citing works
Sun, X., Cao, B., Naval-Sánchez, M., Pham, T. A., Sun, Y., Williams, B., Heazlewood, S. Y., Deshpande, N., Li, J., Kraus, F., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22863-0 · Cited by 118 · see citing works
Poscablo, D. M., Worthington, A. K., Smith‐Berdan, S., Rommel, M. G. E., Manso, B. A., Adili, R., Mok, L., Reggiardo, R. E., Cool, T., Mogharrab, R., et al. (2024) · Cell · doi:10.1016/j.cell.2024.04.018 · Cited by 116 · see citing works
“19,20 21–24 This age-related functional decline of old HSCs (oHSCs) stands in stark contrast to our recently uncovered surprising gain of function of old MkPs (oMkPs) compared with young MkPs (yMkPs).”
ResultLimited rejuvenation of aged hematopoietic stem cells in young bone marrow niche
Kuribayashi, W., Oshima, M., Itokawa, N., Koide, S., Nakajima-Takagi, Y., Yamashita, M., Yamazaki, S., Rahmutulla, B., Miura, F., Ito, T., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20192283 · Cited by 111 · see citing works
Stem Cells, Redox Signaling, and Stem Cell Aging
Liang, R., & Ghaffari, S. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5300 · Cited by 106 · see citing works
“Aging is associated with HSC expansion, compromise of their homing, gradual loss of their function, HSC myeloid biased-differentiation, and onset of anemia (20, 93, 103).”
Inflammation in atherosclerosis: Lessons and therapeutic implications
Libby, P., & Soehnlein, O. (2025) · Immunity · doi:10.1016/j.immuni.2025.09.012 · Cited by 115 · see citing works
Singh, S. K., Williams, C. A., Klarmann, K. D., Burkett, S. S., Keller, J. R., & Oberdoerffer, P. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20121608 · Cited by 107 · see citing works
“Similar observations have been made for myc- or glucocorticoid receptor-associated H4 acetylation, which is necessary but not sufficient to induce transcription of target genes (Frank et al., 2001; Flavin et al., 2004).”
BackgroundWahlestedt, M., Norddahl, G. L., Sten, G., Ugale, A., Frisk, M.-A. M., Mattsson, R., Deierborg, T., Sigvardsson, M., & Bryder, D. (2013) · Blood · doi:10.1182/blood-2012-11-469080 · Cited by 106 · see citing works
“For instance, the key epigenetic regulator Ezh2 is down-regulated in aged HSCs.36 Although we previously found little evidence of epigenetic changes at the p16INK4a locus in aged HSCs,36 a wellestablished Ezh2 target loci in other cells,37 the broad and potent roles of Ezh2 might well underlie other epigenetic alterat…”
ResultInfluentialClonal hematopoiesis, somatic mosaicism, and age-associated disease
Evans, M. A., & Walsh, K. (2022) · Physiological Reviews · doi:10.1152/physrev.00004.2022 · Cited by 105 · see citing works
HSC Aging and Senescent Immune Remodeling
Denkinger, M. D., Leins, H., Schirmbeck, R., Florian, M. C., & Geiger, H. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.10.008 · Cited by 105 · see citing works
“It is currently unclear whether the aging-associated myeloid bias of hematopoiesis is a consequence of such a clonal shift, or whether aging directly impacts on the differentiation potential of HSCs themselves [53].”
Fujino, T., Goyama, S., Sugiura, Y., Inoue, D., Asada, S., Yamasaki, S., Matsumoto, A., Yamaguchi, K., Isobe, Y., Tsuchiya, A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22053-y · Cited by 101 · see citing works
Young, K. A., Borikar, S., Bell, R. K., Kuffler, L., Philip, V. M., & Trowbridge, J. J. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20160168 · Cited by 102 · see citing works
Dysregulation of Systemic Immunity in Aging and Dementia
Lutshumba, J., Nikolajczyk, B. S., & Bachstetter, A. D. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.652111 · Cited by 103 · see citing works
Hennrich, M. L., Romanov, N., Horn, P., Jaeger, S., Eckstein, V., Steeples, V., Ye, F., Ding, X., Poisa-Beiro, L., Lai, M. C., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06353-4 · Cited by 101 · see citing works
Kirschner, K., Chandra, T., Kiselev, V. Y., Cruz, D. F. S., Macaulay, I. C., Park, H. J., Li, J., Kent, D. G., Kumar, R., Pask, D. C., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.04.074 · Cited by 98 · see citing works
“In addition to the lineage skew, aging of the hematopoietic system also results in reduced performance in blood reconstitution and engraftment, regardless of lineage output (Dykstra et al., 2011).”
BackgroundAging-induced IL27Ra signaling impairs hematopoietic stem cells
He, H., Xu, P., Zhang, X., Liao, M., Dong, Q., Cong, T., Tang, B., Yang, X., Ye, M., Chang, Y., et al. (2020) · Blood · doi:10.1182/blood.2019003910 · Cited by 94 · see citing works
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Pharmacological Regulation of Oxidative Stress in Stem Cells
Lee, J., Cho, Y. S., Jung, H., & Choi, I. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/4081890 · Cited by 94 · see citing works
The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience
Wrona, M. V., Ghosh, R. B., Coll, K., Chun, C., & Yousefzadeh, M. J. (2024) · Frontiers in Aging · doi:10.3389/fragi.2024.1490302 · Cited by 102 · see citing works
“Beyond the differentiation bias aged HSCs are also known to have an inferior potential for immune reconstitution, engraftment, and self-renewal compared to younger HSCs (Morrison et al., 1996; Dykstra et al., 2011).”
BackgroundDo haematopoietic stem cells age?
Dorshkind, K. A., Höfer, T., Montecino‐Rodriguez, E., Pioli, P. D., & Rodewald, H.-R. (2019) · Nature reviews. Immunology · doi:10.1038/s41577-019-0236-2 · Cited by 93 · see citing works
B lymphocyte-derived acetylcholine limits steady-state and emergency hematopoiesis
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Epigenetic traits inscribed in chromatin accessibility in aged hematopoietic stem cells
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Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1
Renders, S., Svendsen, A. F., Panten, J., Rama, N., Maryanovich, M., Sommerkamp, P., Ladel, L., Redavid, A. R., Gibert, B., Lazare, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20801-0 · Cited by 83 · see citing works
- Authors
- Dykstra, B., Olthof, S., Schreuder, J., Ritsema, M., & de Haan, G.
- Affiliations
- University Medical Center Groningen (NL)
- Department of Cell Biology 1 ; and 2
- Corresponding author
- Dykstra, Brad
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2011-11-21
- Volume
- 208
- Issue
- 13
- Pages
- 2691-2703
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3244040
- OpenAlex
- W2103911902
- Cited by
- 494
- References
- 38
- Citations by year
- 2026: 26 · 2025: 34 · 2024: 35 · 2023: 42 · 2022: 38 · 2021: 42 · 2020: 41 · 2019: 36 · 2018: 40 · 2017: 26 · 2016: 36 · 2015: 25 · 2014: 29 · 2013: 29 · 2012: 15
- FWCI
- 15.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- The Journal of Experimental Medicine (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-sa)
- Funders
- Ministry of Earth Sciences
- Universitair Medisch Centrum Groningen
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- hematopoietic stem cells, aging, clonal analysis, HSC self-renewal, stromal co-culture, serial transplantation, cellular aging
- MeSH terms
- Animals, Antigens, Differentiation, Colony-Forming Units Assay, Hematopoietic Stem Cells, Mice, Transgenic, Transplantation, Homologous, Cellular Senescence, Hematopoietic Stem Cell Transplantation, Cell Proliferation, Mice
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