p16INK4a Is a Key Downstream Mediator of the Deleterious Effects of FoxO Deficiency on Maintenance of the Hematopoietic Stem Cell Compartment.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1405-1405
Author(s):  
Zuzana Tothova ◽  
Stephen M Sykes ◽  
Dena S Leeman ◽  
James W Horner ◽  
Norman Sharpless ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Accelerated Aging ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Downstream Mediator

Abstract Regulation of oxidative stress in the hematopoietic stem cell (HSC) compartment is critical for the maintenance of HSC self-renewal. A number of reports have previously implicated p16 in aging of HSCs, pancreatic β-islet cells and subventricular zone progenitors in the brain [1–3]. In the context of the hematopoietic system, p16INK4a expression in HSCs increases with age, and correlates with decreased HSC repopulating ability, decreased self-renewal, and increased apoptosis with stress [1]. We and others have recently reported that FoxO play essential roles in the response to physiologic oxidative stress and thereby mediate quiescence and enhanced survival in the HSC compartment [4, 5]. Young mice deficient in FoxO1, FoxO3, and FoxO4 in the adult hematopoietic system, with striking similarity to aging wild-type mice, show a defect in bone marrow repopulating ability, decrease in self-renewal, myeloid skewing in differentiation and increased levels of apoptosis. Furthermore, young FoxO-deficient HSC show increased levels of p16 when compared to their wildtype counterparts. These collective findings suggested the possibility that FoxO loss could result in accelerated aging of HSC due to increased expression of p16 as a consequence of increased ROS. To test the hypothesis that p16 is one of the key mediators of FoxO loss responsible for accelerated aging of HSC, we deleted FoxO1, FoxO3, and FoxO4 in the adult hematopoietic system of mice deficient in p16INK4a. Young mice deficient in FoxO and p16 shared the same characteristics of their HSC(Lin−Sca1+c-kit+) compartment as mice deficient in FoxO only, including decreased number of HSC, increased percentage of HSC entering S/G2/M and apoptosis, and increased levels of ROS as compared to their wildtype counterparts. However, in a setting of long-term repopulation studies, bone marrow isolated from mice deficient in p16 and FoxO demonstrated a rescue of long-term repopulation for up to 20 weeks, as compared to FoxO deficient bone marrow that showed a severe defect in long-term repopulation. p16 deficiency in the setting of FoxO deficiency did not result in reduction of ROS levels in the HSC compartment. Taken together, these findings indicate that p16 is a critical downstream mediator of FoxO in the maintenance of the HSC compartment, and that it can dissociate the detrimental effects of ROS on HSC self-renewal in a setting of FoxO deficiency.

scholarly journals Osteoblast ablation reduces normal long-term hematopoietic stem cell self-renewal but accelerates leukemia development

Blood ◽  
2015 ◽  
Vol 125 (17) ◽  
pp. 2678-2688 ◽  
Author(s):  
Marisa Bowers ◽  
Bin Zhang ◽  
Yinwei Ho ◽  
Puneet Agarwal ◽  
Ching-Cheng Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem Cell ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Key Points ◽  
Leukemia Development

Key Points Bone marrow OB ablation leads to reduced quiescence, long-term engraftment, and self-renewal capacity of hematopoietic stem cells. Significantly accelerated leukemia development and reduced survival are seen in transgenic BCR-ABL mice following OB ablation.

G-CSF Treatment Induces Hematopoietic Stem Cell Quiescence but Loss of Repopulating Activity

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1206-1206
Author(s):  
Joshua N. Borgerding ◽  
Priya Gopalan ◽  
Matthew Christopher ◽  
Daniel C. Link ◽  
Laura G. Schuettpelz
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Inflammatory Signaling ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
A Cell

Abstract Abstract 1206 There is accumulating evidence that systemic signals, such as inflammatory cytokines, can affect hematopoietic stem cell (HSC) function. Granulocyte colony stimulating factor (G-CSF), the principal cytokine regulating granulopoiesis, is often induced in response to infection or inflammation. Additionally, G-CSF is the most commonly used agent for HSC mobilization prior to stem cell transplantation. Recently there has been a renewed interest in the use of “G-CSF primed bone marrow” for stem cell transplantation, so understanding the affect of G-CSF on bone marrow HSCs is clinically relevant. Because the G-CSF receptor is expressed on HSCs, and G-CSF creates biologically relevant modifications to the bone marrow microenvironment, we hypothesized that increased signaling through G-CSF may alter the repopulating and/or self-renewal properties of HSCs. Due to G-CSF's role as an HSC mobilizing agent, we predicted that the number of HSCs in the bone marrow would be reduced after 7 days of G-CSF treatment. Surprisingly, we observe that stem cell numbers markedly increase, regardless of which HSC-enriched population is analyzed. C-kit+lineage−sca+CD34− (KLS-34−), KLS CD41lowCD150+CD48− (KLS-SLAM), and KLS-SLAM CD34− increase by 6.97±2.25 fold, 1.79±0.29 fold, and 2.08±0.39 fold, respectively. To assess HSC repopulating activity, we conducted competitive bone marrow transplants. Donor mice were treated with or without G-CSF for 7 days, and bone marrow was transplanted in a 1:1 ratio with marrow from untreated competitors into lethally irradiated congenic recipients. Compared to untreated HSCs, we found that G-CSF treated cells have significantly impaired long-term repopulating and self-renewal activity in transplanted mice. In fact, on a per cell basis, the long-term repopulating activity of KLS-CD34− cells from G-CSF treated mice was reduced approximately 13 fold. The loss of repopulating activity per HSC was confirmed by transplanting purified HSCs. Homing experiments indicate that this loss of function is not caused by an inability to home from the peripheral blood to the bone marrow niche. As HSC quiescence has been positively associated with repopulating activity, we analyzed the cell cycle status over time of KLS-SLAM cells treated with G-CSF. This analysis revealed that after a brief period of enhanced cycling (69.8±5.0% G0 at baseline; down to 55.9±4.1% G0after 24 hours of G-CSF), treated cells become more quiescent (86.8±2.8% G0) than untreated HSCs. A similar increase in HSC quiescence was seen in KLS-34− cells. Thus our data show that G-CSF treatment is associated with HSC cycling alterations and function impairment. Because G-CSF is associated with modifications to the bone marrow microenvironment, and the microenvironment is known to regulate HSCs at steady state, we asked whether the G-CSF induced repopulating defect was due to a cell intrinsic or extrinsic (secondary to alterations in the microenvironment) mechanism. To do this, we repeated the competitive transplantation experiments using chimeric mice with a mixture of wild-type and G-CSF receptor knockout (Csf3r−/−) bone marrow cells. We find that only the repopulating activity of HSCs expressing the G-CSF receptor is affected by G-CSF, suggesting a cell-intrinsic mechanism. To identify targets of G-CSF signaling that may mediate loss of stem cell function, we performed RNA expression profiling of sorted KSL-SLAM cells from mice treated for 36 hours or seven days with or without G-CSF. The profiling data show that G-CSF treatment is associated with activation of inflammatory signaling in HSCs. Studies are in progress to test the hypothesis that activation of specific inflammatory signaling pathways mediates the inhibitory effect of G-CSF on HSC function. In summary, G-CSF signaling in HSCs, although associated with increased HSC quiescence, leads to a marked loss of long-term repopulating activity. These data suggest that long-term engraftment after transplantation of G-CSF-primed bone marrow may be reduced and requires careful follow-up. Disclosures: No relevant conflicts of interest to declare.

Pivotal Role for Gsk3 in Hematopoietic Stem Cell Homeostasis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1292-1292
Author(s):  
Jian Huang ◽  
Peter S. Klein
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Signaling Pathways ◽  
Hematopoietic Stem Cell ◽  
Pivotal Role ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Gsk3 Inhibitor

Abstract Abstract 1292 Hematopoietic stem cells (HSCs) maintain the ability to self-renew and to differentiate into all lineages of the blood. The signaling pathways regulating hematopoietic stem cell (HSCs) self-renewal and differentiation are not well understood. We are very interested in understanding the roles of glycogen synthase kinase-3 (Gsk3) and the signaling pathways regulated by Gsk3 in HSCs. In our recent study (Journal of Clinical Investigation, December 2009) using loss of function approaches (inhibitors, RNAi, and knockout) in mice, we found that Gsk3 plays a pivotal role in controlling the decision between self-renewal and differentiation of HSCs. Disruption of Gsk3 in bone marrow transiently expands HSCs in a μ-catenin dependent manner, consistent with a role for Wnt signaling. However, in long-term repopulation assays, disruption of Gsk3 progressively depletes HSCs through activation of mTOR. This long-term HSC depletion is prevented by mTOR inhibition and exacerbated by μ-catenin knockout. Thus GSK3 regulates both Wnt and mTOR signaling in HSCs, with opposing effects on HSC self-renewal such that inhibition of Gsk3 in the presence of rapamycin expands the HSC pool in vivo. These findings identify unexpected functions for GSK3 in HSC homeostasis, suggest a therapeutic approach to expand HSCs in vivo using currently available medications that target GSK3 and mTOR, and provide a compelling explanation for the clinically prevalent hematopoietic effects of lithium, a widely prescribed GSK3 inhibitor. In the following study, we found that the combination of Gsk3 inhibitor and mTOR inhibitor can expand phenotypic HSCs in vivo and maintain functional HSC in ex vivo culture. This study will provide the basis for a new clinical approach to improve the efficiency of bone marrow transplantation. Disclosures: Klein: Follica: Consultancy.

Alcam Mediated Cellular Interaction Regulates Hematopoietic Stem Cell Repopulation and Self-Renewal

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1291-1291
Author(s):  
Robin Jeannet ◽  
Qi Cai ◽  
Hongjun Liu ◽  
Hieu Vu ◽  
Ya-Huei Kuo
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cell Surface ◽  
Hematopoietic Stem Cell ◽  
Cellular Interaction ◽  
Mrna Levels ◽  
Wild Type ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract Abstract 1291 Alcam, which encodes the activated leukocyte cell adhesion molecule (CD166), is a cell surface immunoglobulin superfamily member mediating homophilic adhesion as well as heterotypic interactions with CD6. It has recently been shown that Alcam+ endosteal subset in the bone marrow contain hematopoietic niche cells able to support hematopoietic stem cell (HSC) activity. We examined Alcam mRNA levels and cell surface expression by quantitative RT-PCR and flow cytometry in various hematopoietic stem and progenitor subsets. We found that Alcam is highly expressed in long-term repopulating HSC (LT-HSC), multipotent progenitors (MPP), and granulocyte/macrophage progenitors (GMP). We use an Alcam null mouse allele to assess the function of Alcam in HSC differentiation and self-renewal. Clonogenic colony-forming progenitor serial-replating assay show that the replating potential of Alcam-deficient LT-HSCs is impaired. An in vitro single-cell differentiation assay of phenotypic LT-HSCs reveals that Alcam-deficiency leads to an enhanced granulocytic differentiation. In competitive repopulation transplantation, Alcam-deficient cells show a transient engraftment enhancement, however, the engraftment is significantly lower in secondary transplantation, suggesting that the self-renewal capacity of Alcam-deficient HSC is compromised. We performed a limiting-dilution transplantation assay and determined that the frequency of long-term repopulating cells in Alcam-deficient bone marrow is significantly reduced compared to wild type control. We further assessed the engraftment efficiency of phenotypically purified LT-HSCs. We show that the engraftment efficiency of Alcam-deleted LT-HSCs is significantly reduced compared to wild type LT-HSCs. Since Alcam-deleted HSCs are able to home efficiently to the bone marrow cavity, the engraftment defect is not due to inefficient homing upon transplantation. Collectively, These studies implicate Alcam mediated cell-cell interaction in the regulation of hematopoietic transplantation and recovery. Disclosures: No relevant conflicts of interest to declare.

Enhanced Notch Signaling Skews Hematopoietic Stem Cell Differentiation in Fanconi Anemia Murine Models

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1191-1191
Author(s):  
Wei Du ◽  
Jared Sipple ◽  
Jonathan Schick ◽  
Qishen Pang
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Stem Cell ◽  
Notch Signaling ◽  
Hematopoietic Stem Cell ◽  
Fanconi Anemia ◽  
Gfp Expression ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract Abstract 1191 Objective: Hematopoietic stem cells (HSCs) can either self-renew or differentiate into various types of cells of the blood lineage. Little is known about the signaling pathways that regulate this choice of self-renewal versus differentiation. We studied the effect of altered Notch signaling on HSC differentiation in mouse models of Fanconi anemia (FA), a genetic disorder associated with bone marrow failure and progression to leukemia and other cancers. Methods: The study used a Notch reporter mouse, in which Notch-driven GFP expression acts as a sensor for HSC differentiation. Long-term hematopoietic stem cell (LT-HSC) and multipotential progenitor (MPP) cell compartments, as well as GFP expression in different cell populations were detected by Flow Cytometry analysis using primary bone marrow cells from Notch-eGFP-WT, Notch-eGFP-Fanca−/− or Notch-eGFP-Fancc−/− mice. Cell Cycle analysis was performed to distinguish the difference of quiescent state in GFP-gated LSK cells from these Notch-eGFP reporter mice. Colony forming units (CFU) assay and bone marrow transplantation (BMT) were utilized to determine HSC self-renew capacity. Gene arrays for pathways involved in DNA repair, cell cycle control, anti-oxidant defense, inflammatory response and apoptotic signaling were employed to define the gene expression signatures of the MPP population. Results and conclusions: In mice expressing a transgenic Notch reporter, deletion of the Fanca or Fancc gene enhanced Notch signaling in MPPs, which was correlated with decreased phenotypic long-term HSCs and increased formation of MPP1 progenitors. Furthermore, we found a functional correlation between Notch signaling and self-renewal capacity in FA hematopoietic stem and progenitor cells (HSPCs). Significantly, we show that FA deficiency in MPPs deregulates a complex network of genes in the Notch and canonical NF-kB pathways. Specifically, enhanced Notch signaling in FA MPPs was associated with the unregulation of genes involved in inflammatory and stress responses (including Rela, Tnfrsf1b, Gadd45b, Sod2, Stat1, Irf1 and Xiap), cell-cycle regulation (including Ccnd1, Cdc16, Cdkn1a, Gsk3b, Notch2 and Nr4a2), and transcription regulation (including Rela, Stat1, Hes1, Hey1, Hoxb4, Notch1 and Notch2). Consequently, TNF-a stimulation enhanced Notch signaling of FA LSK cells, leading to decreased HSC quiescence and compromised HSC self-renewal. Finally, genetic ablation of NF-kB reduced Notch signaling in FA MPPs to nearly wide-type level, and blocking either NF-kB or Notch signaling partially restored FA HSC quiescence and self-renewal capacity. Translational Applicability: The study identifies a functional interaction between the FA pathway and Notch signaling in HSC differentiation and establishes a role of FA proteins in the control of balance between renewal and lineage commitment, hence contributing to hematopoiesis. These findings indicate that the Notch signaling pathway may represent a novel and therapeutically accessible pathway in FA. Disclosures: No relevant conflicts of interest to declare.

The p110α Catalytic Isoform of PI3 Kinase Is Important for Erythropoiesis, but Has a Minimal Role in Hematopoietic Stem Cell Self-Renewal.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3620-3620
Author(s):  
Kira Gritsman ◽  
Tulasi Khandan ◽  
Rachel Okabe ◽  
Maricel Gozo ◽  
Mahnaz Paktinat ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Cells ◽  
Pi3 Kinase ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Counts

Abstract Abstract 3620 Poster Board III-556 PIK3CA, which encodes the p110α catalytic isoform of PI3 kinase (PI3K), is mutated in many human cancers, and is an attractive therapeutic target. However, PI3K may also be important during hematopoiesis, as it is activated by hematopoietic growth factor receptors which control hematopoietic stem cell (HSC) and progenitor proliferation, differentiation, and self-renewal, such as erythropoietin receptor (epoR), c-kit receptor, and fms-like tyrosine kinase 3 (FLT3). In hematopoietic cells, receptor tyrosine kinases signal through the catalytic p110 subunit of PI3K, which has 3 isoforms (α, β, δ). However, the roles of PI3K and its specific catalytic isoforms in normal HSC function are poorly understood. We hypothesized that signaling through the p110α isoform is important for hematopoiesis and HSC self-renewal. We have used the Cre-loxP system to delete p110α in the HSCs of adult mice by breeding p110αF/F mice to Mx1-Cre transgenic mice. p110αF/F;Mx1-Cre+ (Cre+) mice and their p110αF/F (Cre-) littermates were injected with PolyI-PolyC (pIpC) at 4-6 weeks of age to induce Cre-mediated excision at the PIK3CA locus specifically in hematopoietic cells. Deletion of p110α in the bone marrow (BM) was verified by PCR and by immunoblot. We observed that, by four weeks after pIpC treatment, Cre+ mice developed microcytic anemia compared with Cre- littermates, characterized by a decreased mean hemoglobin (p<0.0001) and decreased mean corpuscular volume, while white blood cell counts and platelet counts were unaffected. Cre+ mice also had significantly decreased spleen, liver, and thymus weights. Flow cytometry analyses of bone marrow and spleen cells revealed a relative block in erythropoiesis in the spleens of Cre+ mice, with expansion of the basophilic erythroblast population, and a decrease in the most mature nucleated erythroblast population. Colony assays of splenocytes in erythropoietin-containing methylcellulose medium revealed a 52% decrease in BFU-E colony formation by p110α-deleted cells in response to erythropoietin, suggesting that loss of p110α may lead to blunted epoR signaling (p=0.009). Multiparameter flow cytometry revealed that the overall number of Lin-Sca1+ckit+ (LSK) cells, which contains the HSC population, was increased two-fold in the BM of Cre+ mice compared with Cre- littermates (p=0.01). To determine whether loss of p110α affects long-term HSC self-renewal in vivo, we performed competitive repopulation assays, in which CD45.2+ BM cells from PIPC-treated Cre+ mice or Cre- controls were transplanted together with CD45.1+CD45.2+ competitor BM cells into lethally irradiated CD45.1+ recipient mice. Donor BM chimerism (%CD45.2+ cells) at 16 weeks was mildly reduced in the absence of p110α, but Cre+ cells were still capable of long-term reconstitution. In summary, we have found that the p110α catalytic isoform is specifically required for erythropoiesis, but has only a small role in HSC homeostasis and in differentiation of the other hematopoietic lineages. This suggests that pharmacologic targeting of p110α in cancer therapy may result in mild anemia, but should otherwise have minimal hematologic toxicity. Disclosures: Gilliland: Merck Research Laboratories: Employment. Roberts:Novartis Pharmaceuticals, Inc.: Consultancy. Zhao:Novartis Pharmaceuticals, Inc.: Consultancy.

scholarly journals Wnt-5A/B Signaling in Hematopoiesis throughout Life

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1801
Author(s):  
Marina Mastelaro de Rezende ◽  
Giselle Zenker Justo ◽  
Edgar Julian Paredes-Gamero ◽  
Reinoud Gosens
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Hematopoietic Stem Cell ◽  
Current Knowledge ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Myeloid Development ◽  
Dependent Pathway

Wnt signaling is well-known to play major roles in the hematopoietic system, from embryogenesis to aging and disease. In addition to the main β-catenin-dependent pathway, it is now clear that Wnt5a and the structurally related Wnt5b are essential for hematopoiesis, bone marrow colonization and the final steps of hematopoietic stem cell (HSC) maturation via β-catenin-independent signaling. Wnt5a and Wnt5b ligands prevent hematopoietic exhaustion (by maintaining quiescent, long-term HSCs), induce the proliferation of progenitors, and guide myeloid development, in addition to being involved in the development of aging-related alterations. The aim of this review is to summarize the current knowledge on these roles of Wnt5a and Wn5b signaling in the hematopoietic field.

The histone lysine acetyltransferase HBO1 (KAT7) regulates hematopoietic stem cell quiescence and self-renewal

Blood ◽  
2021 ◽  
Author(s):  
Yuqing Yang ◽  
Andrew J Kueh ◽  
Zoe Grant ◽  
Waruni Abeysekera ◽  
Alexandra L Garnham ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Hematopoietic Stem Cell ◽  
Cell Function ◽  
Bone Marrow Cells ◽  
High Rate ◽  
Embryonic Patterning ◽  
Self Renewal ◽  
Hematopoietic Stem

The histone acetyltransferase HBO1 (MYST2, KAT7) is indispensable for postgastrulation development, histone H3 lysine 14 acetylation (H3K14Ac) and the expression of embryonic patterning genes. In this study, we report the role of HBO1 in regulating hematopoietic stem cell function in adult hematopoiesis. We used two complementary cre-recombinase transgenes to conditionally delete Hbo1 (Mx1-Cre and Rosa26-CreERT2). Hbo1 null mice became moribund due to hematopoietic failure with pancytopenia in the blood and bone marrow two to six weeks after Hbo1 deletion. Hbo1 deleted bone marrow cells failed to repopulate hemoablated recipients in competitive transplantation experiments. Hbo1 deletion caused a rapid loss of hematopoietic progenitors (HPCs). The numbers of lineage-restricted progenitors for the erythroid, myeloid, B-and T-cell lineages were reduced. Loss of HBO1 resulted in an abnormally high rate of recruitment of quiescent hematopoietic stem cells (HSCs) into the cell cycle. Cycling HSCs produced progenitors at the expense of self-renewal, which led to the exhaustion of the HSC pool. Mechanistically, genes important for HSC functions were downregulated in HSC-enriched cell populations after Hbo1 deletion, including genes essential for HSC quiescence and self-renewal, such as Mpl, Tek(Tie-2), Gfi1b, Egr1, Tal1(Scl), Gata2, Erg, Pbx1, Meis1 and Hox9, as well as genes important for multipotent progenitor cells and lineage-specific progenitor cells, such as Gata1. HBO1 was required for H3K14Ac through the genome and particularly at gene loci required for HSC quiescence and self-renewal. Our data indicate that HBO1 promotes the expression of a transcription factor network essential for HSC maintenance and self-renewal in adult hematopoiesis.

scholarly journals FOXO activity adaptation safeguards the hematopoietic stem cell compartment in hyperglycemia

2020 ◽  
Vol 4 (21) ◽  
pp. 5512-5526
Author(s):  
Vinothini Govindarajah ◽  
Jung-Mi Lee ◽  
Michael Solomon ◽  
Bryan Goddard ◽  
Ramesh Nayak ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cell ◽  
Stress Response ◽  
Hematopoietic Stem Cell ◽  
Adaptive Strategy ◽  
Oxidative Stress Response ◽  
Obese Mice ◽  
Hematopoietic Stem ◽  
Metabolic Stresses

Abstract Hematopoietic stem cell (HSC) activity is tightly controlled to ensure the integrity of the hematopoietic system during the organism’s lifetime. How the HSC compartment maintains its long-term fitness in conditions of chronic stresses associated with systemic metabolic disorders is poorly understood. In this study, we show that obesity functionally affects the long-term function of the most immature engrafting HSC subpopulation. We link this altered regenerative activity to the oxidative stress and the aberrant constitutive activation of the AKT signaling pathway that characterized the obese environment. In contrast, we found minor disruptions of the HSC function in obese mice at steady state, suggesting that active mechanisms could protect the HSC compartment from its disturbed environment. Consistent with this idea, we found that FOXO proteins in HSCs isolated from obese mice become insensitive to their normal upstream regulators such as AKT, even during intense oxidative stress. We established that hyperglycemia, a key condition associated with obesity, is directly responsible for the alteration of the AKT-FOXO axis in HSCs and their abnormal oxidative stress response. As a consequence, we observed that HSCs isolated from a hyperglycemic environment display enhanced resistance to oxidative stress and DNA damage. Altogether, these results indicate that chronic metabolic stresses associated with obesity and/or hyperglycemia affect the wiring of the HSCs and modify their oxidative stress response. These data suggest that the uncoupling of FOXO from its environmental regulators could be a key adaptive strategy that promotes the survival of the HSC compartment in obesity.

scholarly journals Clonal-level lineage commitment pathways of hematopoietic stem cells in vivo

2019 ◽  
Vol 116 (4) ◽  
pp. 1447-1456 ◽  
Author(s):  
Rong Lu ◽  
Agnieszka Czechowicz ◽  
Jun Seita ◽  
Du Jiang ◽  
Irving L. Weissman
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem Cell ◽  
Lineage Commitment ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Different Levels

While the aggregate differentiation of the hematopoietic stem cell (HSC) population has been extensively studied, little is known about the lineage commitment process of individual HSC clones. Here, we provide lineage commitment maps of HSC clones under homeostasis and after perturbations of the endogenous hematopoietic system. Under homeostasis, all donor-derived HSC clones regenerate blood homogeneously throughout all measured stages and lineages of hematopoiesis. In contrast, after the hematopoietic system has been perturbed by irradiation or by an antagonistic anti-ckit antibody, only a small fraction of donor-derived HSC clones differentiate. Some of these clones dominantly expand and exhibit lineage bias. We identified the cellular origins of clonal dominance and lineage bias and uncovered the lineage commitment pathways that lead HSC clones to different levels of self-renewal and blood production under various transplantation conditions. This study reveals surprising alterations in HSC fate decisions directed by conditioning and identifies the key hematopoiesis stages that may be manipulated to control blood production and balance.

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