The staying power of hematopoietic stem cells

Hematopoietic stem and progenitor cells (HSPCs) use specialized adhesive structures referred to as magnupodium to stay in hematopoietic niches. Bessey et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.202005085) define new characteristics of the magnupodium, including centriole polarization and the necessary and sufficient role of CXCR4 signaling.

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The Making of Hematopoiesis: Developmental Ancestry and Environmental Nurture

International Journal of Molecular Sciences ◽

10.3390/ijms19072122 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2122 ◽

Cited By ~ 7

Author(s):

Geoffrey Brown ◽

Rhodri Ceredig ◽

Panagiotis Tsapogas

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Cell Fate ◽

Hematopoietic Stem ◽

Fate Determination ◽

Intermediate Progenitors ◽

Lineage Tree ◽

Stem And Progenitor Cells ◽

The Many

Evidence from studies of the behaviour of stem and progenitor cells and of the influence of cytokines on their fate determination, has recently led to a revised view of the process by which hematopoietic stem cells and their progeny give rise to the many different types of blood and immune cells. The new scenario abandons the classical view of a rigidly demarcated lineage tree and replaces it with a much more continuum-like view of the spectrum of fate options open to hematopoietic stem cells and their progeny. This is in contrast to previous lineage diagrams, which envisaged stem cells progressing stepwise through a series of fairly-precisely described intermediate progenitors in order to close down alternative developmental options. Instead, stem and progenitor cells retain some capacity to step sideways and adopt alternative, closely related, fates, even after they have “made a lineage choice.” The stem and progenitor cells are more inherently versatile than previously thought and perhaps sensitive to lineage guidance by environmental cues. Here we examine the evidence that supports these views and reconsider the meaning of cell lineages in the context of a continuum model of stem cell fate determination and environmental modulation.

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Kinetics of normal hematopoietic stem and progenitor cells in a Notch1-induced leukemia model

Blood ◽

10.1182/blood-2009-06-227843 ◽

2009 ◽

Vol 114 (18) ◽

pp. 3783-3792 ◽

Cited By ~ 41

Author(s):

Xiaoxia Hu ◽

Hongmei Shen ◽

Chen Tian ◽

Hui Yu ◽

Guoguang Zheng ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Quiescent State ◽

Hematopoietic Stem ◽

Definitive Evidence ◽

Accelerated Proliferation ◽

Stem And Progenitor Cells ◽

Underlying Mechanisms ◽

The Impact

Abstract The predominant outgrowth of malignant cells over their normal counterparts in a given tissue is a shared feature for all types of cancer. However, the impact of a cancer environment on normal tissue stem and progenitor cells has not been thoroughly investigated. We began to address this important issue by studying the kinetics and functions of hematopoietic stem and progenitor cells in mice with Notch1-induced leukemia. Although hematopoiesis was progressively suppressed during leukemia development, the leukemic environment imposed distinct effects on hematopoietic stem and progenitor cells, thereby resulting in different outcomes. The normal hematopoietic stem cells in leukemic mice were kept in a more quiescent state but remained highly functional on transplantation to nonleukemic recipients. In contrast, the normal hematopoietic progenitor cells in leukemic mice demonstrated accelerated proliferation and exhaustion. Subsequent analyses on multiple cell-cycle parameters and known regulators (such as p21, p27, and p18) further support this paradigm. Therefore, our current study provides definitive evidence and plausible underlying mechanisms for hematopoietic disruption but reversible inhibition of normal hematopoietic stem cells in a leukemic environment. It may also have important implications for cancer prevention and treatment in general.

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Malignant Myeloma Cells Impair Phenotype and Function of stem and Progenitor Cells.

Blood ◽

10.1182/blood.v114.22.1799.1799 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1799-1799

Author(s):

Ingmar Bruns ◽

Sebastian Büst ◽

Akos G. Czibere ◽

Ron-Patrick Cadeddu ◽

Ines Brückmann ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Plasma Cells ◽

Self Renewal ◽

Hematopoietic Stem ◽

Healthy Donors ◽

Stem And Progenitor Cells

Abstract Abstract 1799 Poster Board I-825 Multiple myeloma (MM) patients often present with anemia at the time of initial diagnosis. This has so far only attributed to a physically marrow suppression by the invading malignant plasma cells and the overexpression of Fas-L and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by malignant plasma cells triggering the death of immature erythroblasts. Still the impact of MM on hematopoietic stem cells and their niches is scarcely established. In this study we analyzed highly purified CD34+ hematopoietic stem and progenitor cell subsets from the bone marrow of newly diagnosed MM patients in comparison to normal donors. Quantitative flowcytometric analyses revealed a significant reduction of the megakaryocyte-erythrocyte progenitor (MEP) proportion in MM patients, whereas the percentage of granulocyte-macrophage progenitors (GMP) was significantly increased. Proportions of hematopoietic stem cells (HSC) and myeloid progenitors (CMP) were not significantly altered. We then asked if this is also reflected by clonogenic assays and found a significantly decreased percentage of erythroid precursors (BFU-E and CFU-E). Using Affymetrix HU133 2.0 gene arrays, we compared the gene expression signatures of stem cells and progenitor subsets in MM patients and healthy donors. The most striking findings so far reflect reduced adhesive and migratory potential, impaired self-renewal capacity and disturbed B-cell development in HSC whereas the MEP expression profile reflects decreased in cell cycle activity and enhanced apoptosis. In line we found a decreased expression of the adhesion molecule CD44 and a reduced actin polymerization in MM HSC by immunofluorescence analysis. Accordingly, in vitro adhesion and transwell migration assays showed reduced adhesive and migratory capacities. The impaired self-renewal capacity of MM HSC was functionally corroborated by a significantly decreased long-term culture initiating cell (LTC-IC) frequency in long term culture assays. Cell cycle analyses revealed a significantly larger proportion of MM MEP in G0-phase of the cell cycle. Furthermore, the proportion of apoptotic cells in MM MEP determined by the content of cleaved caspase 3 was increased as compared to MEP from healthy donors. Taken together, our findings indicate an impact of MM on the molecular phenotype and functional properties of stem and progenitor cells. Anemia in MM seems at least partially to originate already at the stem and progenitor level. Disclosures Off Label Use: AML with multikinase inhibitor sorafenib, which is approved by EMEA + FDA for renal cell carcinoma.

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Jarid2 regulates hematopoietic stem cell function by acting with polycomb repressive complex 2

Blood ◽

10.1182/blood-2014-10-603969 ◽

2015 ◽

Vol 125 (12) ◽

pp. 1890-1900 ◽

Cited By ~ 22

Author(s):

Sarah A. Kinkel ◽

Roman Galeev ◽

Christoffer Flensburg ◽

Andrew Keniry ◽

Kelsey Breslin ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Hematopoietic Stem Cell ◽

Cell Function ◽

Hematopoietic Stem ◽

Polycomb Repressive Complex 2 ◽

Key Points ◽

Stem And Progenitor Cells

Key Points Depletion of Jarid2 in mouse and human hematopoietic stem cells enhances their activity. Jarid2 acts as part of PRC2 in hematopoietic stem and progenitor cells.

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Restriction of expression of an integrated recombinant retrovirus in primary but not immortalized murine hematopoietic stem cells

Blood ◽

10.1182/blood.v71.6.1738.1738 ◽

1988 ◽

Vol 71 (6) ◽

pp. 1738-1743 ◽

Cited By ~ 12

Author(s):

DA Williams ◽

B Lim ◽

E Spooncer ◽

J Longtine ◽

TM Dexter

Keyword(s):

Stem Cells ◽

Enzyme Activity ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Pluripotent Stem Cell ◽

Sv40 Promoter ◽

Hematopoietic Stem ◽

Human Enzyme ◽

Stem And Progenitor Cells

Abstract A recombinant retrovirus (DHFR*-SVADA) in which human adenosine deaminase (ADA) cDNA is transcribed from an internal SV40 promoter was used to infect murine hematopoietic stem and progenitor cells. Human ADA enzyme was not expressed in infected primary murine pluripotent stem cell-derived spleen or progenitor colonies (CFU-GM, CFU-Mix, BFU- E). In contrast, human ADA enzyme activity was readily detected in progenitor colonies derived from immortalized multipotent factor- dependent cells. The level of human enzyme was near endogenous murine enzyme levels and was equivalent in undifferentiated stem cells and differentiated myeloid, erythroid, and mixed colonies. These results indicate that cellular properties other than the stage of differentiation are important in determining the expression of foreign sequences introduced by retroviruses. Cell lines that are immortalized but still capable of induced differentiation may contain factors that abrogate blocks to expression that are manifested in primary hematopoietic stem cells.

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Change in SP Distribution with Age Reflects Intrinsic Age-Based Changes in Stem Cell Biology: Implications for the Mechanism of Aging.

Blood ◽

10.1182/blood.v106.11.4209.4209 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4209-4209

Author(s):

Daniel J. Pearce ◽

Catherine Simpson ◽

Kirsty Allen ◽

Ayad Eddaoudi ◽

Derek Davies ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Cell Biology ◽

Stem Cell Biology ◽

Hematopoietic Stem ◽

Stem And Progenitor Cells ◽

The Absolute

Abstract It has been postulated that as we age, accumulated damage causes stem cells to die by apoptosis. This could lead to a diminished stem cell pool and consequently a reduced organ regeneration potential that contributes to somatic senescence. Hematopoietic stem cells have evolved many mechanisms to cope with their exposure to toxins during life. Cell surface transporters and anti-toxic enzymes are highly expressed in hematopoietic stem cells. If toxins do get the opportunity to damage the DNA of stem cells then the cell is more likely to die by apoptosis than attempt DNA repair and risk an error. Summarised below are our results from an investigation of the frequency, phenotype, cell cycle status and repopulation potential (in young recipients) of C57BL6 side population (SP) cells from mice with a range of ages. The absolute frequency of SP cells increases with age (Figure-A). The proportion of the lineage negative, Sca-1+, c-kit+ (KLS) cell population that is an SP stem cell increases from ~1% to over 30% during the murine lifetime (red bars in Figure-B). These SP cells from older mice have a reduced 4-month competitive repopulation potential when compared to SP cells from younger mice but contain a similarly low proportion of phenotypically-defined mature cells (blue bars in Figure-B) and have a similar cell cycle profile and progenitor cell output (2% of 3 x 96 well plates for each). SP cells from older mice contained a higher proportion of SP cells with the highest efflux ability (61 vs 414 days, p=<0.001, n=6) Engrafted cells derived from old SP cells 4 months previously still displayed an increased SP frequency when compared to engrafted cells derived from SP cells of young mice. Hence, more progenitors or committed cells have not gained the SP ability; rather this difference in SP distribution reflects an age-dependent change in hematopoietic stem cell biology that is independent of the microenvironment. Specifically, the proportion of stem and progenitor cells (KLS) that is a stem cell (SP fraction of KLS) increases with age. We hypothesize that this may be a progressive enrichment of primitive cells over time via selection. As we age, accumulative damage to hematopoietic stem and progenitor cells causes more cells to die by apoptosis. It may be that the stem/progenitor cells with the lowest hoechst efflux ability are most susceptible to damage and hence most likely to die by apoptosis. Since the HSCs with the highest efflux of hoechst are thought to be the most primitive, it may be that there is an enrichment of primitive cells. This could account for the increased SP proportion observed within KLS cells. As there may be cells with ABC/G2 activity that is undetectable via the SP technique, selection of cells with a higher pump activity could also explain the increased SP frequency we observed. This hypothetical mechanism would also be independent of microenvirinment. In summary, we surmise that HSCs have a mechanism that copes with cellular damage while compensating for the reduced cellular output of HSCs with age by increasing the absolute number of HSCs. Figure Figure

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Inactivation of PUMA Protects Hematopoietic Stem Cells and Confers Long Term Survival in Response to High Dose γ-Irradiation

Blood ◽

10.1182/blood.v112.11.612.612 ◽

2008 ◽

Vol 112 (11) ◽

pp. 612-612 ◽

Cited By ~ 1

Author(s):

Hui Yu ◽

Hongmei Shen ◽

Feng Xu ◽

Xiaoxia Hu ◽

Yanxin Li ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Radiation Injury ◽

Γ Irradiation ◽

Hematopoietic Stem ◽

Cycle Arrest ◽

Stem And Progenitor Cells ◽

Radiation Induced

Abstract Radiation injury remains a significant health problem. New medical intervention to prevent or manage radiation damage is highly dependent on a deeper understanding of how radiation-induced cell death is accomplished in the irradiated tissue cells such as stem and progenitor cells. To date, relatively specific or untainted molecular mediators in apoptosis of tissue stem and progenitor cells upon radiation injury have not been clearly defined. The p53 pathway is known as a major molecular mechanism for cell apoptosis, upon the exposure of lethal radiation. Targeting p53 confers a radioprotective effect, but may increase tumorigenesis due to impaired cell cycle arrest for DNA repair. In our current study, we have examined the specific role of PUMA (p53 up-regulated mediator of apoptosis) in the radiosensitivity of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). By quantitative RT PCR, we found that the level of PUMA mRNA was relatively low in the most primitive long-term repopulating hematopoietic stem cells (LT-HSC, isolated based on the immnunophenotype “CD34−LKS”) as compared to other hematopoietic cell populations from mice, but it was significantly elevated in response to γ-irradiation. In the mice lacking PUMA, while neither HSC number nor HSC function was altered under homeostatic conditions, the PUMA−/− HSCs appeared to be resistant to radiation damage in vivo as retrospectively quantified in a competitive HSC transplant model. Our further direct measurement with a single cell culture system for HSC growth in vitro, demonstrated that PUMA, but not p21 (the chief mediator of p53 in cell cycle arrest), is primarily responsible for the radiosensitivity of HSC in the p53 pathway (200 LT-HSCs analyzed for each cell type). Together, these data provide definitive evidence for PUMA as an essential mediator in radiation-induced apoptosis of tissue stem cells. We finally focused on the beneficial effects of targeting PUMA in HSCs and HPCs on the animal survival upon the exposure of lethal irradiation. Strikingly, the wild-type mice reconstituted with PUMA−/− hematopoietic cells exhibited a significant survival advantage after two rounds of 9-Gy γ-irradiation (18 Gy in total) as compared to the mice reconstituted with PUMA+/+ hematopoietic cells (95 % vs. 0 % survival in 20 days, n=21/each group; 50% vs. 0 % survival in 180 days, n=20 or 11/each group, respectively) as shown in the figure below. Moreover, unlike the p53−/− mice, those PUMA−/− reconstituted mice did not have an increased incidence of hematopoietic malignancies (n=20) within 180 days. Therefore, our current study establishes PUMA as an attractive molecular target for the development of therapeutic agents for the prevention and treatment of radiation injury.

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Acute exercise mobilizes hematopoietic stem and progenitor cells and alters the mesenchymal stromal cell secretome

Journal of Applied Physiology ◽

10.1152/japplphysiol.00925.2015 ◽

2016 ◽

Vol 120 (6) ◽

pp. 624-632 ◽

Cited By ~ 27

Author(s):

Russell Emmons ◽

Grace M. Niemiro ◽

Olatomide Owolabi ◽

Michael De Lisio

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Stromal Cells ◽

Acute Exercise ◽

Marrow Cell ◽

Exercise Bout ◽

Hematopoietic Stem ◽

Stem And Progenitor Cells

Transplantation of hematopoietic stem and progenitor cells (HSPC), collected from peripheral blood, is the primary treatment for many hematological malignancies; however, variable collection efficacy with current protocols merits further examination into factors responsible for HSPC mobilization. HSPCs primarily reside within the bone marrow and are regulated by mesenchymal stromal cells (MSC). Exercise potently and transiently mobilizes HSPCs from the bone marrow into peripheral circulation. Thus the purpose of the present study was to evaluate potential factors in the bone marrow responsible for HSPC mobilization, investigate potential sites of HSPC homing, and assess changes in bone marrow cell populations following exercise. An acute exercise bout increased circulating HSPCs at 15 min (88%, P < 0.001) that returned to baseline at 60 min. Gene expression for HSPC homing factors (CXCL12, vascular endothelial growth factor-a, and angiopoietin-1) were increased at 15 min in skeletal muscle and HSPC content was increased in the spleen 48 h postexercise (45%, P < 0.01). Acute exercise did not alter HSPCs or MSCs quantity in the bone marrow; however, proliferation of HSPCs (40%, P < 0.001), multipotent progenitors (40%, P < 0.001), short-term hematopoietic stem cells (61%, P < 0.001), long-term hematopoietic stem cells (55%, P = 0.002), and MSCs (20%, P = 0.01) increased postexercise. Acute exercise increased the content of the mobilization agent granulocyte-colony stimulating factor, as well as stem cell factor, interleukin-3, and thrombopoeitin in conditioned media collected from bone marrow stromal cells 15 min postexercise. These findings suggest that the MSC secretome is responsible for HSPC mobilization and proliferation; concurrently, HSPCs are homing to extramedullary sites following exercise.

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Thrombopoietin promotes NHEJ DNA repair in hematopoietic stem cells through specific activation of Erk and NF-κB pathways and their target, IEX-1

Blood ◽

10.1182/blood-2013-07-515874 ◽

2014 ◽

Vol 123 (4) ◽

pp. 509-519 ◽

Cited By ~ 27

Author(s):

Bérengère de Laval ◽

Patrycja Pawlikowska ◽

Daniela Barbieri ◽

Corinne Besnard-Guerin ◽

Alba Cico ◽

...

Keyword(s):

Stem Cells ◽

Dna Repair ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Hematopoietic Stem ◽

Key Points ◽

Stem And Progenitor Cells ◽

Common Target

Key Points TPO specifically activates Erk and NF-κB pathways in hematopoietic stem and progenitor cells. Erk and NF-κB cooperate to trigger their common target, Iex-1, and DNA-PK-dependent NHEJ activation in HSPCs upon irradiation.

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CXCR4-SDF-1 Signaling Mediated up-Regulation of Survivin Expression In Mesenchymal Progenitor Cells Is Critical for Their Proliferation and Maintenance of Osteoblastic Niche

Blood ◽

10.1182/blood.v116.21.941.941 ◽

2010 ◽

Vol 116 (21) ◽

pp. 941-941

Author(s):

Pratibha Singh ◽

Jennifer Speth ◽

Peirong Hu ◽

Louis M. Pelus

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Flow Cytometry ◽

Stem Cell ◽

Progenitor Cells ◽

Survivin Expression ◽

Wild Type ◽

Hematopoietic Stem ◽

Cxcr4 Signaling

Abstract Abstract 941 Hematopoietic stem cells reside in osteoblastic and vascular niches within the bone marrow. The osteoblastic niche is composed of mesenchymal stem cell derived progenitor cells (MPC) and osteoblasts and are the main sources of the CXC chemokine CXCL12/SDF-1 in the bone marrow microenvironment. Several published studies suggest that the interaction between CXCR4 expressed on hematopoietic stem cells with SDF-1 produced in the bone marrow microenvironment is important for their retention in the bone-marrow. However, the role of SDF-CXCR4 signaling in formation and maintenance of osteoblastic niches in the bone marrow is not known. In this study, we examined the role of CXCR4 signaling in MPC proliferation and differentiation and its effects on hematopoietic stem cell (HSC) function. Flow cytometry analysis demonstrated that CXCR4 is expressed on the phenotypically defined MPC. Deletion of CXCR4 in tamoxifen cre inducible CXCR4flox-flox mice (verified by PCR and flow cytometry; 90% gene deletion and surface CXCR4 expression) results in significantly decreased numbers of Lin- CD45- CD31- Sca-1+ ALCAM- MPC (39±4.2%) and Lin- CD45- CD31- Sca-1-CD51+ osteoblasts (25±2.6%) in bone marrow 15 days after tamoxifen treatment. SDF-1 induced proliferation of CXCR4 deficient MPC was decreased by 4-fold compared to control, measured by the colony forming unit-fibroblast (CFU-F) assay. To determine, whether CXCR4 deficiency in bone marrow stromal cells affects SDF-1 induced HSC proliferation, we cultured FACS sorted wild-type SLAM SKL (103 cells) on CXCR4 deficient stroma for 5 days and total SLAM SKL cell numbers were counted by flow-cytometey analysis. CXCR4 deficient stroma failed to support optimal HSC proliferation and 48±5.2% less SLAM KSL cells was observed on CXCR4 deficient stroma compared to wild-type stroma. To investigate the mechanisms through which CXCR4-SDF-1 signaling regulates MPC proliferation, we evaluated the effect of SDF-1 treatment on expression of the anti-apoptotic and cell-cycle regulator protein, Survivin, in MPC. Multivariate intracellular flow cytometry demonstrated that Survivin expression increased by 23±4.2% in wild-type MPC after SDF-1 treatment (50ng/ml), however no significant increased was demonstrated in CXCR4 deficient MPC cells. CFU-F formation was reduced by 2.5 fold when the Survivin gene was conditionally deleted in MPC. Moreover, fewer SLAM SKL cells were detected on Survivin deficient stroma compared to wild-type stroma after SDF-1 treatment for 5 days. In conclusion, our data suggest that CXCR4-SDF-1 signaling mediated Survivin expression in MPC is important for their proliferation and maintenance of the bone-marrow hematopoietic niche. Disclosures: No relevant conflicts of interest to declare.

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