scholarly journals Acetyl-CoA Carboxylase 1 Is Essential for Hematopoietic Stem Cell Homeostasis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1083-1083
Author(s):  
Morgan A Jones ◽  
Adam Ross ◽  
Qing Li
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Poly I:C ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Hematopoietic Stem

Abstract Though fatty acid oxidation has been shown to be essential for hematopoietic stem cell maintenance, the importance of fatty acid uptake from the bone marrow microenvironment vs. de novo lipogenesis has not been elucidated. The process of de novo lipogenesis begins with the generation of malonyl-CoA from acetyl-CoA and is catalyzed by the enzyme acetyl-CoA carboxylase 1 (ACC1), encoded by Acaca. In leukemia, both ACC1 activation and degradation of ACC1 have been shown to enhance disease progression, suggesting an important role in leukemogenesis. The function of ACC1 in normal hematopoiesis remains unknown. To characterize the role of ACC1 in normal hematopoiesis, we bred mice that harbored an Acaca allele in which exons 22 through 26 were flanked by loxp sites. We crossed these animals to a mouse line harboring the Mx1-Cre transgene, generating Acaca fl/fl; Mx1-Cre + (ACC1 KO) and Acaca fl/fl; Mx1-Cre -(ACC1 WT) mice. Animals were then treated with intraperitoneal poly(I:C) injection to drive Mx1-Cre expression and Acaca excision. By 4-6 weeks after poly(I:C) injection, ACC1 KO animals developed expansion of hematopoietic stem cells and progenitors, including Lineage - Sca-1 +cKit hi (LSK) and the LSK CD48 -CD150 + long-term hematopoietic stem cell (LT-HSC) populations. In addition, these animals developed splenomegaly with extramedullary LSK expansion and enhanced myelopoiesis. ACC1 KO LSKs showed increased cell cycle activity and LT-HSCs demonstrated a reduced quiescent fraction compared to ACC1 WT controls. These data suggest that ACC1 deficiency results in increased cell cycle activity among primitive hematopoietic progenitors and biases cell fate to the myeloid lineage. To further test the impact of ACC1 deletion on LT-HSC function, we established competitive chimerism maintenance assays in which equal numbers of CD45.2 +Acaca fl/fl; Mx1-Cre +or CD45.2 +Acaca fl/fl; Mx1-Cre - bone marrow cells were mixed with CD45.1 + competitor bone marrow and transplanted into lethally irradiated recipient mice. Transplants were then given 8 weeks to establish stable engraftment. After documenting comparable engraftment, 5-poly(I:C) injections were administered every other day. Over the course of 16 weeks of tracking, the ACC1 KO graft showed a significant reduction in trilineage hematopoietic output as indicated by a reduction in B cell, T cell, and myeloid populations in the peripheral blood. After 16 weeks, animals were sacrificed and the LT-HSC compartment was analyzed, showing a significant reduction in ACC1 KO LT-HSCs. Together, these data suggest that the loss of ACC1 significantly impairs the ability of LT-HSCs to maintain long term hematopoiesis in competitive transplants. Collectively, these data are the first report of a critical role for ACC1 in hematopoiesis and LT-HSC function. Mechanistically, in the absence of ACC1, FACS sorted LSK demonstrated increased ATP content compared to WT controls, suggesting an altered metabolic state in these progenitor cells. Further studies are ongoing to determine if these findings are due to an essential function for ACC1 within the context of de novo lipogenesis, or if ACC1 participates in an as of yet uncharacterized tumor suppressive role. Disclosures No relevant conflicts of interest to declare.

scholarly journals Self-repopulating recipient bone marrow resident macrophages promote long-term hematopoietic stem cell engraftment

Blood ◽  
2018 ◽  
Vol 132 (7) ◽  
pp. 735-749 ◽  
Author(s):  
Simranpreet Kaur ◽  
Liza J. Raggatt ◽  
Susan M. Millard ◽  
Andy C. Wu ◽  
Lena Batoon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Cell Engraftment ◽  
Key Points ◽  
Bone Marrow Engraftment

Key Points Recipient macrophages persist in hematopoietic tissues and self-repopulate via in situ proliferation after syngeneic transplantation. Targeted depletion of recipient CD169+ macrophages after transplant impaired long-term bone marrow engraftment of hematopoietic stem cells.

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.

Ionizing Radiation Induces Hematopoietic Stem Cell Senescence and Long-Term Bone Marrow Suppression in a p16Ink4a/Arf-Independent manner

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1345-1345
Author(s):  
Lijian Shao ◽  
Wei Feng ◽  
Hongliang Li ◽  
Yong Wang ◽  
Norman Sharpless ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Ionizing Radiation ◽  
Hematopoietic Stem Cell ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Sublethal Dose ◽  
Independent Manner ◽  
Hematopoietic Stem

Abstract Abstract 1345 Many patients receiving chemotherapy and/or ionizing radiation (IR) develop residual (or long-term) bone marrow (BM) injury that can not only limit the success of cancer treatment but also adversely affect their quality of life. Although residual BM injury has been largely attributed to the induction of hematopoietic stem cell (HSC) senescence, neither the molecular mechanisms by which chemotherapy and/or IR induce HSC senescence have been clearly defined, nor has an effective treatment been developed to ameliorate the injury. The Ink4a-Arf locus encodes two important tumor suppressors, p16Ink4a (p16) and Arf. Both of them have been implicated in mediating the induction of cellular senscence in a variety of cells including HSCs. Therefore, we examined the role of p16 and/or Arf in IR-induced HSC senescence and long-term BM suppression using a total body irradiation (TBI) mouse model. The results from our studies show that exposure of wild-type (WT) mice to a sublethal dose (6 Gy) of TBI induces HSC senescence and long-term BM suppression. The induction of HSC senescence is not associated with a reduction in telemore length in HSCs and their progeny, but is associated with significant increases in the production of reactive oxygen species (ROS), the expression of p16 and Arf mRNA, and the activity of senescence-associated β-galacotosidase (SA-β-gal) in HSCs. However, genetical deletion of Ink4a and/or Arf has no effect on TBI-induced HSC senescence, as HSCs from the Ink4a and/or Arf knockout mice after exposure to TBI exhibit similar changes as those seen in the cells from irradiated WT mice in comparison with the cells from un-irradiated mice with correspondent genotypes. In addition, TBI-induced long-term BM suppression is also not attenuated by the deletion of the Ink4a and/or Arf genes. These findings suggest that IR induces HSC senescence and long-term BM suppression in a p16Ink4a/Arf-independent manner. Disclosures: No relevant conflicts of interest to declare.

Murine hematopoietic stem cell characterization and its regulation in BM transplantation

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3016-3022 ◽  
Author(s):  
Yi Zhao ◽  
Yuanguang Lin ◽  
Yuxia Zhan ◽  
Gengjie Yang ◽  
Jeffrey Louie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cell Sorting ◽  
Cell Subset ◽  
Transplant Recipients ◽  
Hematopoietic Stem ◽  
Murine Hematopoietic Stem Cell

Using 5-color fluorescence-activated cell sorting, we isolated a subset of murine pluripotent hematopoietic stem cells (PHSC) with the phenotype Lin− Sca+ kit+CD38+ CD34− that appears to fulfill the criteria for most primitive PHSC. In the presence of whole bone marrow (BM) competitor cells, these cells produced reconstitution in lethally irradiated primary, secondary, and tertiary murine transplant recipients over the long term. However, these cells alone could not produce reconstitution in lethally irradiated recipients. Rapid proliferation of these cells after BM transplantation required the assistance of another BM cell subset, which has the phenotype Lin− Sca+ kit+ CD38−CD34+.

scholarly journals Ontogeny of hematopoietic stem cell development: reciprocal expression of CD33 and a novel molecule by maturing myeloid and erythroid progenitors

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 792-799
Author(s):  
C Brashem-Stein ◽  
DA Flowers ◽  
FO Smith ◽  
SJ Staats ◽  
RG Andrews ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Bone Marrow Culture ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Selective Expression ◽  
Reciprocal Expression

We have identified a molecule expressed by human marrow granulocyte/monocyte colony-forming cells (CFU-GM), erythroid colony- forming cells (CFU-E), and erythroid burst-forming units (BFU-E), but not their precursors detectable in long-term bone marrow culture. This antigen, detected by flow microfluorimetry using monoclonal antibody 7B9, is coexpressed with CD33 on many CD34+ CFCs, although only the 7B9 antigen was detected on a portion of BFU-E and CFU-E, whereas only CD33 was found on a portion of CFU-GM. Antibody 7B9 appears to be useful for isolating subsets of progenitors based on their common or selective expression of 7B9 antigen and CD33.

scholarly journals Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization

2020 ◽  
Author(s):  
Ka-Won Kang ◽  
Seung-Jin Lee ◽  
Ji Hye Kim ◽  
Byung-Hyun Lee ◽  
Seok Jin Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Cd34 Cells

Abstract Background This study assessed the mechanism of hematopoietic stem cell (HSC) mobilization using etoposide with granulocyte-colony stimulating factor (G-CSF) and determined how it differed from that using cyclophosphamide with G-CSF or G-CSF alone.Methods The study analyzed data from 173 non-Hodgkin’s lymphoma patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT), in vitro experiments using HSCs and bone marrow stromal cells (BMSCs), and in vivo mouse model studies.Results The etoposide with G-CSF mobilization group showed the highest yield of CD34+ cells and the lowest change in white blood cell counts during mobilization. Etoposide triggered interleukin (IL)-8 secretion from BMSCs and caused long-term BMSC toxicity, which were not observed with cyclophosphamide treatment. The expansion of CD34+ cells cultured in BMSC-conditioned medium containing IL-8 was more remarkable than that without IL-8. The expression of CXCR2, mTOR, and cMYC in HSCs was gradually enhanced at 1, 6, and 24 h after IL-8 stimulation. In animal studies, the etoposide with G-CSF mobilization group presented stronger expression of IL-8-related cytokines and MMP9 and scantier expression of SDF-1 in the bone marrow, compared to the other groups not treated with etoposide.Conclusion Collectively, the unique mechanism of etoposide with G-CSF-mediated mobilization is associated with the secretion of IL-8 from BMSCs, causing the enhanced proliferation and mobilization of HSCs in the bone marrow, which was not observed in the mobilization using cyclophosphamide with G-CSF or G-CSF alone. Moreover, the long-term toxicity of etoposide to BMSC emphasizes the need for further studies to develop more efficient and safe chemo-mobilization strategies.

scholarly journals Primitive human hematopoietic precursors express Bcl-x but not Bcl-2

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 868-876 ◽  
Author(s):  
JR Park ◽  
ID Bernstein ◽  
DM Hockenbery
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cell Population ◽  
Precursor Cells ◽  
Stem Cell Population ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Hematopoietic Precursor

Bcl-2 and its homologue, bcl-xL, encode membrane-associated proteins that suppress programmed cell death of hematopoietic cell lines after growth factor withdrawal, and are expressed in hematopoietic precursor cells. To better understand the maintenance of long-term survival in the hematopoietic stem cell population, we evaluated the expression patterns of Bcl-2 and Bcl-x in primitive hematopoietic precursor populations. Hematopoietic precursor cells expressing CD34 (CD34+) and lacking maturation-linked surface antigens (lin-) were isolated from adult human bone marrow using two-color immunofluorescence cell sorting and fractionated on the basis of forward light scatter characteristics into blast-sized and small to medium lymphocyte-sized cell populations. Bcl-2 expression was shown in 78% to 90% of CD34+ lin- blast-sized cells versus less than 10% of small to medium lymphocyte-sized CD34+ lin- cells by immunohistochemical analysis. Small to medium lymphocyte- sized CD34+ lin- cells were further enriched for primitive precursors by selecting cells that lacked expression of CD38 (CD34+ lin- CD38-). In parallel experiments, only 1% to 4% of CD34+ lin- CD38- cells expressed Bcl-2, whereas 45% to 56% of these cells generated colony- forming cells. In contrast, > or = 94% of cells in all bone marrow subpopulations studied expressed Bcl-x protein. Both alternatively spliced bcl-x transcripts, bcl-xL and bcl-xs, were present. Our data show that the most primitive hematopoietic precursors express Bcl-x but not Bcl-2. Thus, the functional bcl-2 homologue, bcl-xL, may be essential for the long-term survival of the hematopoietic stem cell population.

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