LDL and HDL Counteract Hematopoietic Stem/Progenitor Cells in Regulation of Inflammation and Atherosclerosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1288-1288
Author(s):  
Yingmei Feng
Keyword(s):  
Progenitor Cells ◽  
High Fat Diet ◽  
Conflicts Of Interest ◽  
Density Lipoprotein ◽  
Brdu Incorporation ◽  
High Fat ◽  
Hematopoietic Stem ◽  
Differential Effects ◽  
And Function ◽  
Opposing Effects

Abstract Abstract 1288 Low-density lipoprotein (LDL) is an independent risk factor in cardiovascular disease. Hypercholesterolemia-associated monocytosis and transformation of monocytes into macrophages are the main features underlying the proatherogenic property of LDL. Different from LDL, high-density lipoprotein (HDL) and its major apolipoprotein, apoA-I, counteract atherosclerosis by reversing cholesterol transport, inhibiting inflammatory cell adhesion to plaques, maintaining endothelial integrity, inhibiting oxidation, and as has recently been shown, suppressing hematopoietic stem cell (HSC) proliferation. As inflammatory cells in atherosclerotic plaques are exclusively derived from hematopoietic stem/progenitor cells (HSPC) in bone marrow (BM), we hypothesized that differential effects of LDL and HDL on HSPC proliferation and differentiation may play a role in atherosclerotic plaque development. We explored the effect of HDL and LDL on HSPC number and function using LDL receptor knockout (LDLr ko) mice, fed with high fat diet, and C57BL/6 mice infused with purified apoA-I and or reconstituted (r)HDL. Compared to mice on normal diet, the number of lineage−/cKit+Sca-1+ (KLS) cells was 5-fold higher in LDLr ko mice on high-fat diet. By contrast, infusion of either 8 mg/kg apoA-I or 8, 12 and 16 mg/kg rHDL decreased the KLS cell frequency in BM. Using BrdU incorporation, we demonstrated that LDL induced but HDL inhibited KLS cell proliferation. When lineage negative cells, exposed to LDL or rHDL were used in competitive repopulation studies, HDL-treated cells supported greater chimerism than untreated controls, whereas LDL-treated cells competed less well. In addition, for HDL-treated Lin− cells, skewing of reconstitution to the B-lymphoid lineage at the expense of the granulocyte/monocyte lineage was seen. In vitro, LDL promoted KLS cell differentiation towards the monocytic lineage, which was abrogated by addition of HDL. In conclusion, LDL and HDL have opposing effects on HSPC number and function. These differential effects may contribute to the opposing effects of HDL and LDL on atherosclerosis development. Disclosures: No relevant conflicts of interest to declare.

scholarly journals FoxM1 Haploinsufficiency Drives Clonal Hematopoiesis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 726-726
Author(s):  
Chunjie Yu ◽  
Yue Sheng ◽  
Zhijian Qian
Keyword(s):  
Cell Cycle ◽  
Progenitor Cells ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Clonal Expansion ◽  
Brdu Incorporation ◽  
Quiescent State ◽  
Dapi Staining ◽  
Hematopoietic Stem ◽  
Increased Risk

Hematopoiesis is an orchestrated process in which hematopoietic stem cells (HSCs) can self-renew and produce all lineages of blood cells. Majority of HSCs are in a quiescent state with a low growth rate. However, some genetic mutations that occur in HSCs impel HSCs to exit the quiescent state and to proliferate excessively, which enables mutant HSCs to outcompete normal HSCs and leads to clonal expansion of mutant HSCs. Myelodysplastic syndromes (MDSs) as a clonal disease, arise from the expansion of mutant HSCs and are characterized by morphologic dysplasia, ineffective hematopoiesis and an increased risk of transformation to acute myeloid leukemia. FoxM1 is one of transcription factors in the family of Fox ('Forkhead box') proteins. Analysis of public database revealed that the expression level of FOXM1 was decreased significantly in CD34 + cells from a subset of patients with MDS as compared to healthy individuals. Thus, we sought to determine whether haploinsufficiency of FOXM1 contributes to the development of MDS in mice. Our study showed that haploinsufficiency of Foxm1 led to an expansion of hematopoietic stem/progenitor cells in mice. Since FoxM1 has previously been implicated in regulation of cell cycle, we determined the cell cycle status of Foxm1 heterozygous HSCs. By BrdU incorporation assay, we showed that Foxm1 heterozygous HSCs have an increased S phase and G2/M phase as compared to control HSCs from wildtype mice. Additional analysis with Hochest33342/Pyronin-Y staining and Ki67/DAPI staining showed a significant decrease in the number of quiescent (G0) cells in Foxm1 heterozygous HSCs as compared to control HSCs. These results suggest that FoxM1 haploinsufficiency promotes HSCs to exit quiescence and to enter cell cycle, thereby leading to exhaustion of HSCs. To further assess the function of Foxm1 heterozygous HSCs in vivo, we performed competitive repopulation assay. We found that Foxm1 haploinsufficiency HSCs exhibited competitive repopulation advantage in the first and secondary recipient mice, but displayed significantly decreased capacity of repopulation in tertiary recipient mice as compared to control HSCs, suggesting that Foxm1 haploinsufficiency promoted clonal expansion of HSCs, which leads to an exhaustion of HSCs eventually. HSC proliferation can be induced by some specific immune effectors such as Toll-like receptor 4 (TLR4). Lipopolysaccharide (LPS) stimulates HSC proliferation by activating TLR4 signaling pathway. Low dose of LPS treatment over time accelerated the development of MDS in mice. Interestingly, low dose of LPS injection chronically induced defects in hematopoiesis in Foxm1 haploinsufficient mice but not the control wildtype mice. Recipient mice transplanted with Foxm1 heterozygous BM cells but not the control BM cells developed MDS-like disease with cytopenia and a decreased number of hematopoietic stem/progenitor cells after LPS stimulation. Moreover, we found that nearly half of aged Foxm1 haploinsufficient mice (20 months) developed splenomegaly. Analysis of histologic sections in Foxm1 haploinsufficient mice showed that the mice developed hematopoietic dysplasia including dysplastic megakaryocytes with bizarre-shaped nuclei in bone marrow and extramedullary hematopoiesis with accumulation of myeloid cells in spleen. RNA-seq analysis indicated that haploinsufficiency of Foxm1 perturbed multiple stem cell-maintenance mechanisms especially in metabolic processes. Taken together, our studies suggest that Foxm1 haploinsufficiency in mice causes clonal expansion of HSCs and promotes MDS-like disease, which underscores the significant role of FOXM1 downregulation in the initiation and development of human MDS. Disclosures No relevant conflicts of interest to declare.

IFNs Upregulate Sca-1 and Block Proliferation in Murine Hematopoietic Stem and Progenitor Cells,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3394-3394
Author(s):  
Kaitlyn Shank ◽  
Yusup Shin ◽  
Carson Wills ◽  
Nicole Cunningham ◽  
Alevtina Domashenko ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Progenitor Cells ◽  
Caspase 3 ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Brdu Incorporation ◽  
Apparent Paradox ◽  
Hematopoietic Stem

Abstract Abstract 3394 Hematopoietic stem cells (HSC) replenish the cellular components of the blood throughout life by a homeostatic process in which the majority of HSCs remain quiescent while a small percentage enter the cell cycle to either self-review or differentiate. During inflammatory responses to infections, Interferons (IFNa, IFNg) perturb HSC homeostasis, presumably in response to the demand for increased numbers of inflammatory cells. Previous studies have highlighted an apparent paradox, i.e. IFNs suppress the proliferation of normally cycling murine hematopoietic progenitor cells (HPCs), yet increase the fraction of normally quiescent Sca+ HSCs that proliferate. To investigate the mechanisms underlying this paradox, we dissected the dynamics of cell surface phenotypes, cell cycle kinetics, pro- and anti-apoptotic pathways within the HSC and HPC compartments in response to pIpC and IFNs both in vivo and in vitro. Forty-eight hours after pIpC injection, bone marrow (BM) cellularity declined by 60%, the proportion of Sca- kit+ HPCs fell from 0.45% to 0.05%, while the proportion of BM cells with the Sca+ kit+ HSC phenotype increased from 0.17 to 0.26%. To determine whether the increase in Sca+kit+ cells was due to proliferation of HSCs or upregulation of Sca-1 on HPCs, we cultured purified CD150+ Sca-Kit+ HPCs and CD150+Sca+kit+ HSCs in vitro with IFNa, IFNg, or PBS. Sca expression was induced on previously Sca- HPCs, and the level of Sca expression on HSCs was also increased. This induction was detectable as early as 6 hours after treatment and accompanied by an increase in Sca mRNA. BrdU incorporation into both HPC and HSC populations decreased from pre-treatment baselines, further indicating that the increase in cells with the HSC phenotype was not due to HSC proliferation, but rather the appearance of cycling HPCs within the HSC staining gate following IFN-induced upregulation of Sca. Staining with FITC-DEVD-FMK identified active cleaved capase-3 in pIpC- or IFN-treated cells, suggesting that the reduced cellularity following IFN reflected a cellular stress that killed Lin+ precursors cells and some HPCs, but spared HSCs. In contrast to lin+kit- precursors, all kit + HPCs and HSCs expressed bcl-2, suggesting that expression of anti-apoptotic proteins may prevent IFN-induced stress from resulting in HSC/HPC apoptosis despite the initial triggering of caspase-3 cleavage. In summary, acute treatment with IFNs has anti-proliferative effects on all hematopoietic cells, including precursors, HPCs and HSCs, with the apparent increase in HSC proliferation the result of HPCs masquerading as Sca+HSCs after exposure to IFN. Unlike precursors, HSCs and some HPCs survive treatment to IFNs despite activation of cleaved caspase-3, possibly due to their expression of bcl-2, and likely related anti-apoptotic regulators. The previously observed increase in HSC proliferation days and weeks following IFN treatment is most likely due to the homeostatic response of HSCs to the depopulation of the precursor and HPCs caused by acute IFN exposure. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Syndecan-2 Surface Expression Identifies Hematopoietic Stem Cells with Increased Repopulating Capacity

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1273-1273 ◽  
Author(s):  
Christina Termini ◽  
Michelle Li ◽  
Joyce Kim ◽  
Liman Zhao ◽  
John P Chute
Keyword(s):  
Progenitor Cells ◽  
Hematopoietic Cell Transplantation ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Surface Expression ◽  
Hematopoietic Cell ◽  
Brdu Incorporation ◽  
Short Term ◽  
Hematopoietic Stem

Abstract Syndecans are transmembrane glycoproteins, which can regulate cell proliferation, growth, and adhesion through interactions with neighboring proteins within the plasma membrane or at the cytoplasmic interface. Although syndecans have been described to regulate aberrant signaling in hematological malignances, the role of syndecans in regulating normal hematopoietic stem cell (HSC) proliferation, differentiation, and self-renewal is largely unknown. We demonstrate that syndecan-1 and syndecan-3 are expressed on the surface of < 10% of murine hematopoietic stem and progenitor cells, whereas, syndecan-4 is expressed on 50% of lineage negative (Lin-) progenitor cells and 98% of c-Kit+Sca-1+Lin- (KSL) hematopoietic stem/progenitor cells, KSL CD34-CD48-CD150+/- short-term HSCs, and 100% of CD34-CD48-CD150+ long-term HSCs. Interestingly, we find that syndecan-2 is expressed by 11% of KSL CD34-CD48-CD150+/- short-term HSCs and 36% of CD34-CD48-CD150+ long-term HSCs. More specifically, our data demonstrate a 15-fold increase in syndecan-2 surface expression on KSL CD34-CD48-CD150+ HSCs compared to Lin- progenitor cells (p<.0001, ****). Collectively, these data suggest that syndecan-2 may be a marker for long-term HSCs. In keeping with this hypothesis, we found that syndecan-2+ CD34- KSL cells produce two-fold more granulocyte, erythrocyte, monocyte, megakaryocyte (GEMM) colonies compared to syndecan-2- CD34- KSL cells (p=.0017, **). Cell cycle analyses revealed a significant increase in BrdU incorporation in syndecan-2+ KSL cells compared to syndecan-2- KSL cells (90% versus 40%, p<.0001, ****). Competitive repopulation assays comparing syndecan-2+ or syndecan-2- CD34- KSL bone marrow cells demonstrated that mice transplanted with syndecan-2+ CD34- KSL cells displayed threefold increased donor multilineage hematopoietic cell repopulation compared to mice transplanted with syndecan-2- CD34- KSL cells. These data suggest that syndecan-2 expression marks a highly proliferative population of HSCs with increased multilineage repopulating capacity and that syndecan-2+ HSCs can be readily isolated to enhance the efficacy of hematopoietic cell transplantation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Metabolic dysfunction induced by high-fat diet modulates hematopoietic stem and myeloid progenitor cells in brown adipose tissue of mice

2021 ◽  
Author(s):  
Kyle T Mincham ◽  
Kunjal Panchal ◽  
Prue H Hart ◽  
Robyn M Lucas ◽  
Martin Feelisch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adipose Tissue ◽  
Progenitor Cells ◽  
Immune Cells ◽  
High Fat Diet ◽  
Low Dose ◽  
Metabolic Dysfunction ◽  
High Fat ◽  
Hematopoietic Stem ◽  
Brown Adipose

AbstractBrown adipose tissue (BAT) may be an important metabolic regulator of whole-body glucose. While important roles have been ascribed to macrophages in regulating metabolic functions in BAT, little known is known of the roles of other immune cells subsets, particularly dendritic cells (DCs). Eating a high fat diet may compromise the development of hematopoietic stem and progenitor cells (HSPC) – which give rise to DCs – in bone marrow, with less known of its effects in BAT. We have previously demonstrated that ongoing exposure to low-dose ultraviolet radiation (UVR) significantly reduced the ‘whitening’ effect of eating a high-fat diet upon interscapular (i)BAT of mice. Here, we examined whether this observation may be linked to changes in the phenotype of HSPC and myeloid-derived immune cells in iBAT and bone marrow of mice using 12-colour flow cytometry. Many HSPC subsets declined in both iBAT and bone marrow with increasing metabolic dysfunction. Conversely, with rising adiposity and metabolic dysfunction, conventional (c)DCs increased in both of these tissues. When compared to low-fat diet, consumption of high-fat diet significantly reduced proportions of myeloid, common myeloid and megakaryocyte-erythrocyte progenitors in iBAT, and short-term hematopoietic stem cells in bone marrow. In mice fed a high-fat diet, exposure to low-dose UVR significantly reduced proportions of cDCs in iBAT, independently of nitric oxide release from irradiated skin (blocked using the scavenger, cPTIO), but did not significantly modify HSPC subsets in either tissue. Further studies are needed to determine whether changes in these cell populations contribute towards metabolic dysfunction.

Maternal High-Fat Diet Persistently Alters Bone Marrow Immune Cell Proportions and Function in a Nonhuman Primate Model

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 222-OR
Author(s):  
MICHAEL J. NASH ◽  
TAYLOR K. SODERBORG ◽  
RACHEL C. JANSSEN ◽  
ERIC M. PIETRAS ◽  
JACOB E. FRIEDMAN
Keyword(s):  
Bone Marrow ◽  
Nonhuman Primate ◽  
High Fat Diet ◽  
Immune Cell ◽  
High Fat ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
And Function

scholarly journals High-fat diet-induced obesity and impairment of brain neurotransmitter pool

2020 ◽  
Vol 11 (1) ◽  
pp. 147-160
Author(s):  
Ranyah Shaker M. Labban ◽  
Hanan Alfawaz ◽  
Ahmed T. Almnaizel ◽  
Wail M. Hassan ◽  
Ramesa Shafi Bhat ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Tissue ◽  
High Fat Diet ◽  
Density Lipoprotein ◽  
Obese Group ◽  
Control Group ◽  
High Fat ◽  
Brain Neurotransmitter ◽  
The Brain ◽  
Lean Group

AbstractObesity and the brain are linked since the brain can control the weight of the body through its neurotransmitters. The aim of the present study was to investigate the effect of high-fat diet (HFD)-induced obesity on brain functioning through the measurement of brain glutamate, dopamine, and serotonin metabolic pools. In the present study, two groups of rats served as subjects. Group 1 was fed a normal diet and named as the lean group. Group 2 was fed an HFD for 4 weeks and named as the obese group. Markers of oxidative stress (malondialdehyde, glutathione, glutathione-s-transferase, and vitamin C), inflammatory cytokines (interleukin [IL]-6 and IL-12), and leptin along with a lipid profile (cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein levels) were measured in the serum. Neurotransmitters dopamine, serotonin, and glutamate were measured in brain tissue. Fecal samples were collected for observing changes in gut flora. In brain tissue, significantly high levels of dopamine and glutamate as well as significantly low levels of serotonin were found in the obese group compared to those in the lean group (P > 0.001) and were discussed in relation to the biochemical profile in the serum. It was also noted that the HFD affected bacterial gut composition in comparison to the control group with gram-positive cocci dominance in the control group compared to obese. The results of the present study confirm that obesity is linked to inflammation, oxidative stress, dyslipidemic processes, and altered brain neurotransmitter levels that can cause obesity-related neuropsychiatric complications.

scholarly journals Effect of Soybean and Soybean Koji on Obesity and Dyslipidemia in Rats Fed a High-Fat Diet: A Comparative Study

2021 ◽  
Vol 18 (11) ◽  
pp. 6032
Author(s):  
Sihoon Park ◽  
Jae-Joon Lee ◽  
Hye-Won Shin ◽  
Sunyoon Jung ◽  
Jung-Heun Ha
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
High Fat Diet ◽  
Unsaturated Fatty Acids ◽  
Density Lipoprotein ◽  
Serum Triglyceride ◽  
Lipoprotein Cholesterol ◽  
Health Concern ◽  
High Fat ◽  
Cholesterol Levels

Soybean koji refers to steamed soybeans inoculated with microbial species. Soybean fermentation improves the health benefits of soybeans. Obesity is a serious health concern owing to its increasing incidence rate and high association with other metabolic diseases. Therefore, we investigated the effects of soybean and soybean koji on high-fat diet-induced obesity in rats. Five-week-old male Sprague-Dawley rats were randomly divided into four groups (n = 8/group) as follows: (1) regular diet (RD), (2) high-fat diet (HFD), (3) HFD + steamed soybean (HFD+SS), and (4) HFD + soybean koji (HFD+SK). SK contained more free amino acids and unsaturated fatty acids than SS. In a rat model of obesity, SK consumption significantly alleviated the increase in weight of white adipose tissue and mRNA expression of lipogenic genes, whereas SS consumption did not. Both SS and SK reduced serum triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels, and increased high-density lipoprotein cholesterol levels. SS and SK also inhibited lipid accumulation in the liver and white adipose tissue and reduced adipocyte size. Although both SS and SK could alleviate HFD-induced dyslipidemia, SK has better anti-obesity effects than SS by regulating lipogenesis. Overall, SK is an excellent functional food that may prevent obesity.

3008 – OXYGEN TENSION REGULATES CALCIUM SIGNALING AND FUNCTION IN HEMATOPOIETIC STEM AND PROGENITOR CELLS

2020 ◽  
Vol 88 ◽  
pp. S40
Author(s):  
Paige Dausinas ◽  
Jacob Slack ◽  
Christopher Basile ◽  
Anish Karlapudi ◽  
Heather O'Leary
Keyword(s):  
Calcium Signaling ◽  
Progenitor Cells ◽  
Oxygen Tension ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
And Function
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