Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 2941-2950 ◽  
Author(s):  
Takashi Yahata ◽  
Tomomi Takanashi ◽  
Yukari Muguruma ◽  
Abd Aziz Ibrahim ◽  
Hideyuki Matsuzawa ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Hematopoietic Stem Cells ◽  
Oxidative Dna Damage ◽  
Major Influence ◽  
Glutathione Synthetase ◽  
Causative Role ◽  
Hematopoietic Stem ◽  
Immunodeficient Mice ◽  
Human Hscs

Abstract Stem cells of highly regenerative organs including blood are susceptible to endogenous DNA damage caused by both intrinsic and extrinsic stress. Response mechanisms to such stress equipped in hematopoietic stem cells (HSCs) are crucial in sustaining hematopoietic homeostasis but remain largely unknown. In this study, we demonstrate that serial transplantation of human HSCs into immunodeficient mice triggers replication stress that induces incremental elevation of intracellular reactive oxygen species (ROS) levels and the accumulation of persistent DNA damage within the human HSCs. This accumulation of DNA damage is also detected in HSCs of clinical HSC transplant patients and elderly individuals. A forced increase of intracellular levels of ROS by treatment with a glutathione synthetase inhibitor aggravates the extent of DNA damage, resulting in the functional impairment of HSCs in vivo. The oxidative DNA damage activates the expression of cell-cycle inhibitors in a HSC specific manner, leading to the premature senescence among HSCs, and ultimately to the loss of stem cell function. Importantly, treatment with an antioxidant can antagonize the oxidative DNA damage and eventual HSC dysfunction. The study reveals that ROS play a causative role for DNA damage and the regulation of ROS have a major influence on human HSC aging.

Engraftment of human hematopoietic stem cells is more efficient in female NOD/SCID/IL-2Rgc-null recipients

Blood ◽  
2010 ◽  
Vol 115 (18) ◽  
pp. 3704-3707 ◽  
Author(s):  
Faiyaz Notta ◽  
Sergei Doulatov ◽  
John E. Dick
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Associated Factors ◽  
Xenograft Model ◽  
Primary Method ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Immunodeficient Mice ◽  
Future Design ◽  
Human Hscs

Abstract Repopulation of immunodeficient mice remains the primary method to assay human hematopoietic stem cells (HSCs). Here we report that female NOD/SCID/IL-2Rgc-null mice are far superior in detecting human HSCs (Lin−CD34+CD38−CD90+CD45RA−) compared with male recipients. When multiple HSCs were transplanted, female recipients displayed a trend (1.4-fold) toward higher levels of human chimerism (female vs male: injected femur, 44.4 ± 9.3 vs 32.2 ± 6.2; n = 12 females, n = 24 males; P = .1). Strikingly, this effect was dramatically amplified at limiting cell doses where female recipients had an approximately 11-fold higher chimerism from single HSCs (female vs male: injected femur, 8.1 ± 2.7 vs 0.7 ± 0.7; n = 28 females, n = 20 males; P < .001). Secondary transplantations from primary recipients indicate that females more efficiently support the self-renewal of human HSCs. Therefore, sex-associated factors play a pivotal role in the survival, proliferation, and self-renewal of human HSCs in the xenograft model, and recipient sex must be carefully monitored in the future design of experiments requiring human HSC assays.

scholarly journals Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region

2011 ◽  
Vol 208 (12) ◽  
pp. 2417-2427 ◽  
Author(s):  
Andrejs Ivanovs ◽  
Stanislav Rybtsov ◽  
Lindsey Welch ◽  
Richard A. Anderson ◽  
Marc L. Turner ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Immunodeficient Mice ◽  
Adult Organism ◽  
Human Hscs ◽  
High Level ◽  
Very High

Hematopoietic stem cells (HSCs) emerge during embryogenesis and maintain hematopoiesis in the adult organism. Little is known about the embryonic development of human HSCs. We demonstrate that human HSCs emerge first in the aorta-gonad-mesonephros (AGM) region, specifically in the dorsal aorta, and only later appear in the yolk sac, liver, and placenta. AGM region cells transplanted into immunodeficient mice provide long-term high level multilineage hematopoietic repopulation. Human AGM region HSCs, although present in low numbers, exhibit a very high self-renewal potential. A single HSC derived from the AGM region generates at least 300 daughter HSCs in primary recipients, which disseminate throughout the entire recipient bone marrow and are retransplantable. These findings highlight the vast regenerative potential of the earliest human HSCs and set a new standard for in vitro generation of HSCs from pluripotent stem cells for the purpose of regenerative medicine.

scholarly journals Using mitochondrial activity to select for potent human hematopoietic stem cells

2021 ◽  
Vol 5 (6) ◽  
pp. 1605-1616
Author(s):  
Jiajing Qiu ◽  
Jana Gjini ◽  
Tasleem Arif ◽  
Kateri Moore ◽  
Miao Lin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Cell Transplantation ◽  
Mitochondrial Activity ◽  
Mitochondrial Morphology ◽  
Blood Disorders ◽  
Hematopoietic Stem ◽  
Immunodeficient Mice ◽  
Human Hscs

Abstract Hematopoietic cell transplantation is a critical curative approach for many blood disorders. However, obtaining grafts with sufficient numbers of hematopoietic stem cells (HSCs) that maintain long-term engraftment remains challenging; this is due partly to metabolic modulations that restrict the potency of HSCs outside of their native environment. To address this, we focused on mitochondria. We found that human HSCs are heterogeneous in their mitochondrial activity as measured by mitochondrial membrane potential (MMP) even within the highly purified CD34+CD38−CD45RA−CD90+CD49f+ HSC population. We further found that the most potent HSCs exhibit the lowest mitochondrial activity in the population. We showed that the frequency of long-term culture initiating cells in MMP-low is significantly greater than in MMP-high CD34+CD38−CD45RA−CD90+ (CD90+) HSCs. Notably, these 2 populations were distinct in their long-term repopulating capacity when transplanted into immunodeficient mice. The level of chimerism 7 months posttransplantation was &gt;50-fold higher in the blood of MMP-low relative to MMP-high CD90+ HSC recipients. Although more than 90% of both HSC subsets were in G0, MMP-low CD90+ HSCs exhibited delayed cell-cycle priming profile relative to MMP-high HSCs. These functional differences were associated with distinct mitochondrial morphology; MMP-low in contrast to MMP-high HSCs contained fragmented mitochondria. Our findings suggest that the lowest MMP level selects for the most potent, likely dormant, stem cells within the highly purified HSC population. These results identify a new approach for isolating highly potent human HSCs for further clinical applications. They also implicate mitochondria in the intrinsic regulation of human HSC quiescence and potency.

scholarly journals Failure of Effector Function of Human CD8+ T Cells in NOD/SCID/JAK3−/− Immunodeficient Mice Transplanted with Human CD34+ Hematopoietic Stem Cells

PLoS ONE ◽  
2010 ◽  
Vol 5 (10) ◽  
pp. e13109 ◽  
Author(s):  
Yoshinori Sato ◽  
Hiroshi Takata ◽  
Naoki Kobayashi ◽  
Sayaka Nagata ◽  
Naomi Nakagata ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Hematopoietic Stem Cells ◽  
Cd8 T Cells ◽  
Effector Function ◽  
Hematopoietic Stem ◽  
Immunodeficient Mice ◽  
Human Cd34

scholarly journals ¬¬Attenuated DNA Damage Responses and Increased Apoptosis Characterize Human Hematopoietic Stem Cells Exposed to Irradiation

2018 ◽  
Vol 64 ◽  
pp. S87
Author(s):  
Michael Milyavsky ◽  
Shahar Biechonski ◽  
Leonid Olender ◽  
Adi Zipin-Roitman ◽  
Muhammad Yassin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Dna Damage Responses

scholarly journals Identification and Age-dependent Increase of Platelet Biased Human Hematopoietic Stem Cells

2022 ◽  
Author(s):  
Merve Aksoz ◽  
Grigore-Aristide Gafencu ◽  
Bilyana Stoilova Stoilova ◽  
Mario Buono ◽  
Yiran Meng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Hematological Malignancies ◽  
Hematopoietic Stem ◽  
Cell Lineages ◽  
Cells Of Origin ◽  
Human Individual ◽  
Age Dependent ◽  
Human Hscs

Hematopoietic stem cells (HSC) reconstitute multi-lineage human hematopoiesis after clinical bone marrow transplantation and are the cells-of-origin of hematological malignancies. Though HSC provide multi-lineage engraftment, individual murine HSCs are lineage-biased and contribute unequally to blood cell lineages. Now, by combining xenografting of molecularly barcoded adult human bone marrow (BM) HSCs and high-throughput single cell RNA sequencing we demonstrate that human individual BM HSCs are also functionally and transcriptionally lineage biased. Specifically, we identify platelet-biased and multi-lineage human HSCs. Quantitative comparison of transcriptomes from single HSCs from young, and aged, BM show that both the proportion of platelet-biased HSCs, and their level of transcriptional platelet priming, increases with age. Therefore, platelet-biased HSCs, as well as their increased prevalence and elevated transcriptional platelet priming during ageing, are conserved between human and murine hematopoiesis.

scholarly journals The replication rate of human hematopoietic stem cells in vivo

Blood ◽  
2011 ◽  
Vol 117 (17) ◽  
pp. 4460-4466 ◽  
Author(s):  
Sandra N. Catlin ◽  
Lambert Busque ◽  
Rosemary E. Gale ◽  
Peter Guttorp ◽  
Janis L. Abkowitz
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cord Blood Transplantation ◽  
Cell Labeling ◽  
Replication Rate ◽  
Hematopoietic Stem ◽  
Daughter Cells ◽  
Blood Transplantation ◽  
Human Hscs

Abstract Hematopoietic stem cells (HSCs) replicate (self-renew) to create 2 daughter cells with capabilities equivalent to their parent, as well as differentiate, and thus can both maintain and restore blood cell production. Cell labeling with division-sensitive markers and competitive transplantation studies have been used to estimate the replication rate of murine HSCs in vivo. However, these methods are not feasible in humans and surrogate assays are required. In this report, we analyze the changing ratio with age of maternal/paternal X-chromosome phenotypes in blood cells from females and infer that human HSCs replicate on average once every 40 weeks (range, 25-50 weeks). We then confirm this estimate with 2 independent approaches, use the estimate to simulate human hematopoiesis, and show that the simulations accurately reproduce marrow transplantation data. Our simulations also provide evidence that the number of human HSCs increases from birth until adolescence and then plateaus, and that the ratio of contributing to quiescent HSCs in humans significantly differs from mouse. In addition, they suggest that human marrow failure, such as the marrow failure that occurs after umbilical cord blood transplantation and with aplastic anemia, results from insufficient numbers of early progenitor cells, and not the absence of HSCs.

Interaction of human hematopoietic stem cells with bacterial pathogens

Blood ◽  
2002 ◽  
Vol 100 (10) ◽  
pp. 3703-3709 ◽  
Author(s):  
Annette Kolb-Mäurer ◽  
Martin Wilhelm ◽  
Florian Weissinger ◽  
Eva-Bettina Bröcker ◽  
Werner Goebel
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Bacterial Infections ◽  
Intracellular Bacteria ◽  
Monocytic Differentiation ◽  
Hematopoietic Stem ◽  
Latex Beads ◽  
Specific Growth Factor ◽  
Bacterial Uptake ◽  
Human Hscs

Primitive hematopoietic stem cells (HSCs) in the bone marrow are rare pluripotent cells with the capacity to give rise to all lineages of blood cells. During commitment, progenitor cells are composed mainly of cells with the potential for differentiation into 1 or 2 lineages. This commitment involves the acquisition of specific growth factor receptors and the loss of others. Viral and bacterial infections may lead to profound disturbance of hematopoiesis, which is possibly due to different susceptibility of HSCs to infectious agents. Here, we show that quiescent human HSCs are fully resistant to infection by the intracellular bacteria, Listeria monocytogenes andSalmonella enterica serovariationtyphimurium, and the extracellular pathogen Yersinia enterocolitica. During myeloid/monocytic differentiation induced by incubation with stem cell factor, thrombopoietin, and flt-3 ligand, partially differentiated HSCs emerge, which readily take up these pathogens and also latex beads by macropinocytosis. After further monocytic differentiation, bacterial uptake by macropinocytosis still occurs but internalization of the pathogens is now mainly achieved by receptor-mediated phagocytosis. These results suggest that in the case of HSCs uptake mechanisms for bacteria develop sequentially.

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