scholarly journals Taurolithocholic acid but not tauroursodeoxycholic acid rescues phagocytosis activity of bone marrow‐derived macrophages under inflammatory stress

2021 ◽  
Author(s):  
Siyu Wu ◽  
Lorenzo Romero‐Ramírez ◽  
Jörg Mey
Keyword(s):  
Bone Marrow ◽  
Tauroursodeoxycholic Acid ◽  
Inflammatory Stress ◽  
Phagocytosis Activity

scholarly journals Imaging the Vascular Bone Marrow Niche During Inflammatory Stress

2018 ◽  
Vol 123 (4) ◽  
pp. 415-427 ◽  
Author(s):  
Katrien Vandoorne ◽  
David Rohde ◽  
Hye-Yeong Kim ◽  
Gabriel Courties ◽  
Gregory Wojtkiewicz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Niche ◽  
Inflammatory Stress

scholarly journals Regeneration-Competent and -Incompetent Murids Differ in Neutrophil Quantity and Function

2019 ◽  
Vol 59 (5) ◽  
pp. 1138-1149 ◽  
Author(s):  
Jennifer L Cyr ◽  
Thomas R Gawriluk ◽  
John M Kimani ◽  
Balázs Rada ◽  
Wendy T Watford ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Reactive Oxygen Species ◽  
Bone Marrow ◽  
Wound Healing ◽  
Whole Blood ◽  
Oxygen Species ◽  
Pathogen Defense ◽  
Bacteria Killing ◽  
And Function ◽  
Phagocytosis Activity

Abstract Regeneration is rare in mammals, but spiny mice (Acomys spp.) naturally regenerate skin and ear holes. Inflammation is thought to inhibit regeneration during wound healing, but aspects of inflammation contribute to both regeneration and pathogen defense. We compared neutrophil traits among uninjured, regeneration-competent (Acomys: A. cahirinus, A. kempi, A. percivali) and -incompetent (Mus musculus: Swiss Webster, wild-caught strains) murids to test for constitutive differences in neutrophil quantity and function between these groups. Neutrophil quantity differed significantly among species. In blood, Acomys had lower percentages of circulating neutrophils than Mus; and in bone marrow, Acomys had higher percentages of band neutrophils and lower percentages of segmented neutrophils. Functionally, Acomys and Mus neutrophils did not differ in their ability to migrate or produce reactive oxygen species, but Acomys neutrophils phagocytosed more fungal zymosan. Despite this enhanced phagocytosis activity, Acomys neutrophils were not more effective than Mus neutrophils at killing Escherichia coli. Interestingly, whole blood bacteria killing was dominated by serum in Acomys versus neutrophils only or neutrophils and serum in Mus, suggesting that Acomys primarily rely on serum to kill bacteria whereas Mus do not. These subtle differences in neutrophil traits may allow regeneration-competent species to offset damaging effects of inflammation without compromising pathogen defense.

Role of Focal Adhesion Kinase in Myelotoxicity, Inflammatory Stress Response and Myeloid Cell Functions.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3615-3615
Author(s):  
Sasidhar Vemula ◽  
Baskar Ramdas ◽  
Philip Hanneman ◽  
Hillary Beggs ◽  
Reuben Kapur
Keyword(s):  
Bone Marrow ◽  
Stress Response ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Peripheral Blood ◽  
Hematopoietic Cells ◽  
Myeloid Cells ◽  
Inflammatory Stress

Abstract Abstract 3615 Poster Board III-551 Focal adhesion kinase (FAK) is a key signaling molecule in focal adhesion signaling and a potential integrator of integrin and growth factor receptor mediated signals. FAK has been implicated in various cellular functions such as growth, survival, migration, adhesion and cytoskeletal reorganization in fibroblasts but its role in hematopoietic stem and progenitors is unknown. To demonstrate the role of FAK in normal and stress-induced hematopoiesis, we generated FAK deficient mice by using a Cre/loxP method from here on termed FAKflox/flox (WT) mice. FAK deletion was induced by injecting poly (I)-poly(C) to FAK flox/flox mice containing the Mx.Cre transgene for one month (FAK-/-). PCR and western blot analysis revealed that after one month of poly (I)-poly(C) induction, hematopoietic cells failed to express detectable levels of FAK in bone marrow (BM), spleen and thymus. To determine the effect of FAK deletion on the development of hematopoietic cells a thorough analysis of the hematopoietic compartment in FAK-/- mice was performed. Total and differential cell counts of peripheral blood revealed significantly high red blood cell distribution width {RDW (%)} and mean cell volume (MCV) in FAK-/- mice compared to WT (n=13, WT; 18.6, 47.2 vs. FAK-/-; 20.06, 48.7, *p<0.05), respectively. In addition, differential basophil counts were significantly less in FAK-/- mice compared to WT (n=13, WT; 0.68 vs. FAK-/-; 0.3 *p<0.04) but all leukocyte populations were present at normal frequencies. Furthermore, platelet counts were significantly higher in FAK-/- peripheral blood compared to WT controls (n=13, WT; 759 vs FAK-/-; 978, *p<0.01). Under basal steady-state conditions, granulopoiesis appeared to be significantly altered in FAK deficient bone marrow (BM), as frequency of granulocytes, but not of other myeloid cells was reduced (n=10, WT; 44.14% vs. FAK-/-; 34.4%, *p<0.0001). Interestingly the frequency of Lin-, c-Kit+, Sca-1+ was also impaired in FAK deficient BM compared to controls (n=9, *p<0.05). FAK deficient BM progenitors displayed significantly lower frequency of colony-forming units compared to WT controls in response to various cytokine combinations (n=6, *p<0.01), which was associated with higher apoptosis in vitro (n=9, *p<0.006). Under conditions of stress, recovery of BM myeloid compartment and Lin−,c-Kit+, Sca-1+ cells following 5-Fluorouracil myeloablation was much slower in FAK-/- mice compared to WT controls (n=3, *p<0.05). Furthermore, the response of myeloid cells to acute inflammatory stress inflicted by intraperitoneal injection of thioglycollate was impaired in FAK-/- mice compared to WT mice (Macrophages: WT; 7.47 × 106 vs. FAK−/−; 3.1 × 106, n=8, *p <0.01. Neutrophils: WT; 5.47 × 106 vs. FAK−/−; 2.1 × 106, n=3, *p <0.05). These results led us to more closely examine the myeloid compartment in these mice. In vitro, FAK-/- macrophage progenitors show reduced growth in response to M-CSF stimulation (n=4, *p <0.01). In addition, deficiency of FAK in macrophages resulted in significant reduction in haptotactic migration in response to M-CSF on extracellular matrix proteins such as fibronectin, laminin and collagen (n=4, *p <0.01). Consistently, a significant reduction in the migration of FAK-/- macrophages was also observed in a wound healing assay which was associated with reduced activation of Rho GTPases including Rac. The reduction in migration of FAK-/- macrophages was associated with a significant decrease in adhesion on fibronectin, laminin and collagen. The impaired migration and adhesion of FAK-/- macrophages was observed in spite of comparable levels of F4/80 as well as integrin (α4β1 & α5β1) expression. Consistent with enhanced neutrophil apoptosis and reduced frequency under basal conditions, FAK deficient BM derived neutrophil progenitors (BMNs) show reduced growth and cycling in response to G-CSF stimulation (n=4, *p <0.01). Deletion of FAK in BMNs led to increased apoptosis upon cytokine withdrawal, which was associated with reduced activation of AKT and increased caspase-3 cleavage compared to controls. Taken together, our findings indicate that FAK plays a vital role in modulating physiological stress response to myeloablation, inflammation as well as in regulating several functions in macrophages and neutrophils. Disclosures: No relevant conflicts of interest to declare.

3015 – INCREASED TGFΒ SIGNALING DRIVES CHRONIC BONE MARROW FAILURE AFTER ACUTE INFLAMMATORY STRESS

2020 ◽  
Vol 88 ◽  
pp. S42
Author(s):  
Jose Javier ◽  
James Bartram ◽  
Dylan David ◽  
Marie-Dominique Filippi ◽  
Ellen Javier ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Tgfβ Signaling ◽  
Inflammatory Stress

Administration of tauroursodeoxycholic acid enhances osteogenic differentiation of bone marrow-derived mesenchymal stem cells and bone regeneration

Bone ◽  
2016 ◽  
Vol 83 ◽  
pp. 73-81 ◽  
Author(s):  
Byung-Hyun Cha ◽  
Moon-Joo Jung ◽  
Bo-Kyung Moon ◽  
Jin-Su Kim ◽  
Yoonji Ma ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Bone Regeneration ◽  
Osteogenic Differentiation ◽  
Tauroursodeoxycholic Acid

scholarly journals Infection Is a Driver of Dnmt3a-Mutant Clonal Hematopoiesis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 817-817
Author(s):  
Daniel Hormaechea Agulla ◽  
Katie A Matatall ◽  
Duy Le ◽  
Bailee Nicole Kain ◽  
Roman Jaksik ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Infection ◽  
Clonal Expansion ◽  
Mutant Population ◽  
Inflammatory Stress ◽  
Clonal Hematopoiesis ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
Minor Population ◽  
Avium Infection

Clonal hematopoiesis of indeterminate potential (CHIP) occurs increasingly with age and is associated with an increase in all-cause mortality. Mutations in DNMT3A, the gene most commonly altered in CHIP, are nearly universal in individuals by the age of 50 but not everyone develops CHIP. This dichotomy suggests that environmental factors likely play a major role in CHIP emergence. However, the environmental drivers of DNMT3A-mutant CHIP have not been determined. Infection has been reported to be epidemiologically linked to a variety of cancers, including acute myelogenous leukemia. In prior work, we demonstrated that systemic chronic infection depletes the hematopoietic stem cell (HSC) pool as a result of excessive differentiation. Since prior studies showed that Dnmt3a-mutant HSCs demonstrate defective differentiation and enhanced self-renewal, we hypothesized that infection may provide an environmental selection pressure to favor the expansion of Dnmt3a-mutant HSCs over their wild-type (WT) counterparts. First, to confirm whether Dnmt3a mutations affect hematologic responses to infection, we infected WT and Mx1-Cre Dnmt3af/f mice, in which Dnmt3a-deletion was induced by PIPC treatment, with M. avium. After four weeks of infection, we found few differences in the number of HSCs, Ki67+ levels, or apoptosis in the blood and bone marrow of WT and Dnmt3a-/- mice. However, Dnmt3a-deficient mice became anemic upon M. avium infection, suggesting a defect in differentiation. To examine the differentiation capacity of DNMT3A-mutant HSCs in response to inflammatory stress, we conducted in vitro differentiation assays with human CD34+ hematopoietic progenitors. Human CD34+ cells in which DNMT3A was disrupted by CRISPR gene editing did not differentiate normally in response to treatment with interferon gamma (IFNy), showing little change in either their HSCs or neutrophil numbers after culture with IFNy compared to control CD34+ cells. These data demonstrate a striking defect in inflammation-induced differentiation in DNMT3A-mutant murine and human HSCs. Next, we utilized a mathematical model to predict the relative prevalence of different populations of HSCs when exposed to the same chronic infectious stress. Specifically, we modeled the behavior of a "minor population" of Dnmt3a-mutant HSCs, compared to a "major population" of WT HSCs. This modeling exercise demonstrated that impaired HSC differentiation in Dnmt3a-mutants during inflammatory stress is sufficient to enable the minor Dnmt3a-mutant HSCs to quickly overtake the major WT population. To test this prediction, we created mosaic mice by transplanting a 1:6 mixture of Dnmt3a-/- and WT competitive WBM into lethally irradiated WT mice. Two months after transplantation, mosaic mice were systemically infected with M. avium, and the infection was allowed to continue for 2 months prior to examining the bone marrow by flow cytometry. In line with the modeling prediction, there was a significant expansion of HSCs only among the infected mosaics containing Dnmt3a-mutant marrow. Expansion of Dnmt3a-mutant cells was also detectible in downstream populations (i.e., multipotent progenitors (MPPs)). Dnmt3a-mutant HSCs expansion was similar upon infection of mosaics created with Vav-Cre Dnmt3af/f donors, where no PIPC-injections are required. To assess the role of IFNy signaling in Dnmt3a-mutant clonal expansion, we infected mosaic mice containing a 1:6 ratio of Dnmt3a-/- IFNyR1-/- DKO to WT HSCs. Strikingly, no clonal expansion was evident among infected mosaics with the DKO minor population, indicating a requirement for IFNy signaling for Dnmt3a-mutant clonal expansion. Next, we conducted RNA-seq to compare the expanded Dnmt3a-mutant population versus an unexpanded Dnmt3a-mutant population. These data showed that, in stark contrast to WT HSCs, the differentiation factor Batf2 was not induced in Dnmt3a-mutant HSCs upon M. avium infection. By using Batf2-/- mice, we found that Batf2-mutant HSCs are resistant to depletion during chronic infection, thus phenocopying Dnmt3a-mutant HSCs In summary, we present the first controlled biological experiment to demonstrate that an environmental factor - infection - can promote Dnmt3a-mutant CHIP. Our studies indicate that a defect in differentiation is sufficient to confer a survival advantage to Dnmt3a-mutant clones during infectious conditions. Disclosures No relevant conflicts of interest to declare.

scholarly journals Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder

2008 ◽  
Vol 205 (3) ◽  
pp. 585-594 ◽  
Author(s):  
Ryan M. O'Connell ◽  
Dinesh S. Rao ◽  
Aadel A. Chaudhuri ◽  
Mark P. Boldin ◽  
Konstantin D. Taganov ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Mouse Bone Marrow ◽  
Pathological Features ◽  
Hematopoietic Stem ◽  
Inflammatory Stress ◽  
Myeloid Neoplasia ◽  
And Function ◽  
Lps Treatment

Mammalian microRNAs are emerging as key regulators of the development and function of the immune system. Here, we report a strong but transient induction of miR-155 in mouse bone marrow after injection of bacterial lipopolysaccharide (LPS) correlated with granulocyte/monocyte (GM) expansion. Demonstrating the sufficiency of miR-155 to drive GM expansion, enforced expression in mouse bone marrow cells caused GM proliferation in a manner reminiscent of LPS treatment. However, the miR-155–induced GM populations displayed pathological features characteristic of myeloid neoplasia. Of possible relevance to human disease, miR-155 was found to be overexpressed in the bone marrow of patients with certain subtypes of acute myeloid leukemia (AML). Furthermore, miR-155 repressed a subset of genes implicated in hematopoietic development and disease. These data implicate miR-155 as a contributor to physiological GM expansion during inflammation and to certain pathological features associated with AML, emphasizing the importance of proper miR-155 regulation in developing myeloid cells during times of inflammatory stress.

scholarly journals Inflammation Mediated Bone Marrow Remodeling

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-2-SCI-2
Author(s):  
Marieke A. G. Essers
Keyword(s):  
Bone Marrow ◽  
Extracellular Matrix ◽  
Stem Cell ◽  
Matrix Protein ◽  
The Body ◽  
Extracellular Matrix Protein ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Inflammatory Stress

Infection is a common, natural form of stress, with which the body is regularly challenged. During infection or inflammation, cells of the immune system are responsible for fighting the invading pathogens. This leads to consumption of blood and immune cells due to mobilization of these cells to the site of infection, or by apoptosis as part of the host response to invading pathogens. Restoration of the balance of the hematopoietic system following successful elimination of the infection is a crucial part of the recovery of the body. In addition, both clinical and experimental data indicate that depending on the scale and duration, infection and inflammation can induce hematopoietic dysfunction compromising immune defense mechanisms and possibly contributing to the development of hematologic malignancies. Restoring the balance of the hematopoietic system depends on the replacement of lost immune cells by the activity of hematopoietic stem cells (HSCs). During the last ten years we and others could show that this so-called emergency hematopoiesis is driven by pro-inflammatory cytokines, who are increasingly produced upon infection or inflammation in the bone marrow and can directly drive the activation of normally quiescent HSCs. An interesting observation from these data is the often opposing impact of these pro-inflammatory cytokines on HSCs in vivo versus in vitro. Whereas in vivo treatment of mice with for example IFNα leads to a strong increase in proliferation of the HSCs, in vitro treatment with IFNα inhibits the HSCs. Furthermore, data from viral infection experiments have shown sustained alterations in the inflammatory cytokine/chemokine profile in the bone marrow weeks after the infection. All these data suggest that interactions of HSCs with their direct environment or signals from this environment are important for a proper response of the HSCs during environmental stress. Research in recent years has focused on unraveling the different components of the HSC stem cell niche. However, the molecular and cellular basis of the BM HSC niche, and signals exchanged between HSC and niche cells under stress conditions remain poorly understood. We initially focused on how the niche responds to inflammatory stress, and could show that the BM stem cell vascular niche was remodeled in response to IFNα. IFNα treatment of mice resulted in increased BM vascularity, expression of key inflammatory and endothelial-stimulatory markers on ECs and increased BM vascular leakiness. These data indicate a novel acute response of the BM vasculature to primary inflammatory signaling, suggesting alterations of the HSC niche in response to stress. ECs are not the only cells in the BM niche responding to inflammatory stress. Using different mouse models and single cell sequencing technology we are currently not only investigating the impact of inflammatory stress on the other components of the niche but also try to unravel the possible changes in interactions and signals between the HSCs and the niche. One example is our data on the role of the extracellular matrix protein Matrilin-4 (Matn4) in the regulation of the HSC response. Under homeostasis high expression of Matn-4 in HSCs confers a resistance to stress stimuli. In situations of acute stress, such as an infection or transplantation, this protection is rapidly lost through down-regulation of Matn-4, allowing HSCs to efficiently replenish the blood system. Thus, these data indicate an important role for the control of the interactions of HSCs with the extracellular matrix in regulating the HSC stress response in vivo. In summary, investigating the response of the bone marrow niche and the role of stem cell-ECM-niche interactions in controlling the HSC stress response will help us to better understand the shortterm and longterm impact of infection and inflammation on the HSCs and their niche. Potential Articles of Interest: Hirche C, Frenz T, Haas S, et al (2017). Systemic Virus Infections differentially modulate Cell Cycle State and Functionality of Long-Term Hematopoietic Stem Cells In Vivo. Cell Reports19: 2345-56Velten L, Haas SF, Raffel S, et al (2017). Human haematopoietic stem cell lineage commitment is a continuous process. Cell Biol.19: 271-281Prendergast AM, Kuck A, van Essen M, et al (2017). IFNa mediated remodeling of endothelial cells in the bone marrow niche. Haematologica,102: 445-453Uckelmann H, Blaszkiewicz S, Nicolae C, et al (2016). Extracellular matrix protein Matrilin-4 regulates stress-induced HSC proliferation via CXCR4. J Exp. Med.213: 1961-1971Haas S, Hansson J, Klimmeck D, et al (2015). Inflammation-induced emergency megakaryopoiesis driven by hematopoietic stem cell-like megakaryocyte progenitors. Cell Stem Cell17: 422-34 Disclosures No relevant conflicts of interest to declare.

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