In VitroStudies on the Sensitivity of Canine Granulopoietic Progenitor Cells (GM-CFC) to Ionizing Radiation: Differences between Steady State GM-CFC from Blood and Bone Marrow

1983 ◽  
Vol 43 (2) ◽  
pp. 133-140 ◽  
Author(s):  
Wilhelm Nothdurft ◽  
Karl-Heinz Steinbach ◽  
Theodor M. Fliedner
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Ionizing Radiation ◽  
Progenitor Cells ◽  
Granulopoietic Progenitor Cells

scholarly journals New pharmacological means of radiation protection (literature review)

2019 ◽  
Author(s):  
Nataliya Uzlenkova
Keyword(s):  
Bone Marrow ◽  
Ionizing Radiation ◽  
Literature Review ◽  
Radiation Exposure ◽  
Progenitor Cells ◽  
Radiation Protection ◽  
Acute Radiation ◽  
Biologically Active ◽  
Pharmacological Agents ◽  
Methodological Approaches

The review systematized the current data on new classes of pharmacological compounds and biologically active substances in the field of radiation protection in Ukraine, as well as abroad. Methodological approaches and the importance of using appropriate animal models in the development of new pharmacological drugs for radiation protection are described, specifically in the cases when it is impossible to conduct full clinical trials on patients. Current views on the division of pharmacological agents into radioprotectors, radiomitigators, and therapeutic radiation protection agents are examined. The changes in the hematopoietic tissue, gastrointestinal tract and neurovascular system that occur after acute radiation exposure are also described. Particular attention is paid to pharmacological agents that can protect against acute exposure to ionizing radiation by limiting the risk of radiation mortality from the hematological and gastrointestinal forms of radiation syndrome. Results of the effectiveness of tolerant antioxidants with a wide spectrum of biological activity as promising agents for the prevention of acute and delayed radiation-induced pathology, in particular, in lung tissue, are presented. Possible molecular mechanisms of the radioprotective effect of pharmacological compounds on experimental models of total and local radiation exposure are discussed. The effectiveness of the therapeutic use of growth factors and recombinant cytokines in acute bone marrow suppression аfter accidental radiation exposure is shown. The possibilities of cell therapy with myeloid progenitor cells mobilized by tocopherol succinate hematopoietic/progenitor cells and bone marrow mesenchymal stromal cells in acute radiation injuries are shown. Special attention is paid to the importance of improving such methodological approaches and regulatory requirements when introducing into practice new radiation protection facilities in Ukraine. Key words: radiation protection, ionizing radiation, pharmacological agents, acute radiation syndrome. For citation: Uzlenkova NE. New pharmacological means of radiation protection (literature review). Journal of the National Academy of Medical Sciences of Ukraine. 2019;25(3) :268–77

Murine Hematopoietic Progenitor Cells With Colony-Forming or Radioprotective Capacity Lack Expression of the β2-Integrin LFA-1

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 107-112 ◽  
Author(s):  
Johannes F.M. Pruijt ◽  
Yvette van Kooyk ◽  
Carl G. Figdor ◽  
Roel Willemze ◽  
Willem E. Fibbe
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Progenitor Cells ◽  
Mononuclear Cells ◽  
Hematopoietic Progenitor Cells ◽  
Colony Stimulating Factor ◽  
Hematopoietic Progenitor ◽  
Β2 Integrin ◽  
Stimulating Factor

Recently, we have demonstrated that antibodies that block the function of the β2-integrin leukocyte function-associated antigen-1 (LFA-1) completely abrogate the rapid mobilization of hematopoietic progenitor cells (HPC) with colony-forming and radioprotective capacity induced by interleukin-8 (IL-8) in mice. These findings suggested a direct inhibitory effect of these antibodies on LFA-1–mediated transmigration of stem cells through the bone marrow endothelium. Therefore, we studied the expression and functional role of LFA-1 on murine HPC in vitro and in vivo. In steady state bone marrow ± 50% of the mononuclear cells (MNC) were LFA-1neg. Cultures of sorted cells, supplemented with granulocyte colony-stimulating factor (G-CSF)/granulocyte-macrophage colony-stimulating factor (GM-CSF)/IL-1/IL-3/IL-6/stem cell factor (SCF) and erythropoietin (EPO) indicated that the LFA-1neg fraction contained the majority of the colony-forming cells (CFCs) (LFA-1neg 183 ± 62/7,500 cells v LFA-1pos 29 ± 17/7,500 cells,P < .001). We found that the radioprotective capacity resided almost exclusively in the LFA-1neg cell fraction, the radioprotection rate after transplantation of 103, 3 × 103, 104, and 3 × 104 cells being 63%, 90%, 100%, and 100% respectively. Hardly any radioprotection was obtained from LFA-1pos cells. Similarly, in cytokine (IL-8 and G-CSF)–mobilized blood, the LFA-1neg fraction, which comprised 5% to 10% of the MNC, contained the majority of the colony-forming cells, as well as almost all cells with radioprotective capacity. Subsequently, primitive bone marrow-derived HPC, represented by Wheat-germ-agglutinin (WGA)+/Lineage (Lin)−/Rhodamine (Rho)− sorted cells, were examined. More than 95% of the Rho− cells were LFA-1neg. Cultures of sorted cells showed that the LFA-1neg fraction contained all CFU. Transplantation of 150 Rho− LFA-1neg or up to 600 Rho−LFA-1pos cells protected 100% and 0% of lethally irradiated recipient mice, respectively. These results show that primitive murine HPC in steady-state bone marrow and of cytokine-mobilized blood do not express LFA-1.

scholarly journals Sphingosine-1-phosphate-Mediated Mobilization of Hematopoietic Stem/Progenitor Cells during Intravascular Hemolysis Requires Attenuation of SDF-1-CXCR4 Retention Signaling in Bone Marrow

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Kasia Mierzejewska ◽  
Yuri M. Klyachkin ◽  
Janina Ratajczak ◽  
Ahmed Abdel-Latif ◽  
Magda Kucia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Progenitor Cells ◽  
Blood Cells ◽  
Blocking Agent ◽  
Intravascular Hemolysis ◽  
Hematopoietic Stem ◽  
Sphingosine 1 Phosphate ◽  
Retention Signal ◽  
Synergistic Increase

Sphingosine-1-phosphate (S1P) is a crucial chemotactic factor in peripheral blood (PB) involved in the mobilization process and egress of hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM). Since S1P is present at high levels in erythrocytes, one might assume that, by increasing the plasma S1P level, the hemolysis of red blood cells would induce mobilization of HSPCs. To test this assumption, we induced hemolysis in mice by employing phenylhydrazine (PHZ). We observed that doubling the S1P level in PB from damaged erythrocytes induced only a marginally increased level of mobilization. However, if mice were exposed to PHZ together with the CXCR4 blocking agent, AMD3100, a robust synergistic increase in the number of mobilized HSPCs occurred. We conclude that hemolysis, even if it significantly elevates the S1P level in PB, also requires attenuation of the CXCR4-SDF-1 axis-mediated retention in BM niches for HSPC mobilization to occur. Our data also further confirm that S1P is a major chemottractant present in plasma and chemoattracts HSPCs into PB under steady-state conditions. However, to egress from BM, HSPCs first have to be released from BM niches by blocking the SDF-1-CXCR4 retention signal.

Bone Marrow Derived Mesenchymal Cells Secrete Granulopoietic Cytokines upon Danger Signaling

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4115-4115
Author(s):  
Stefan Wirths ◽  
Stefanie Bugl ◽  
Markus P. Radsak ◽  
Melanie Märklin ◽  
Martin R. Müller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Progenitor Cells ◽  
Stromal Cells ◽  
Feedback Loop ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Caspase 1 ◽  
Stem And Progenitor Cells ◽  
Myd88 Signaling

Abstract Granulopoietic homeostasis is regulated at steady-state to supply sufficient numbers of pooled and circulating neutrophils to maintain barrier function against commensal flora. In addition, upon pathogenic microbial challenge, an increased formation of neutrophils is induced, termed ‘emergency granulopoiesis’. Antibody-mediated reduction of neutrophil numbers in steady-state induces a feedback loop leading to an increase of bone marrow granulopoiesis with expansion of hematopoetic stem and progenitor cells. This feedback loop was demonstrated to depend on TLR4 and TRIF, but not MyD88 signaling (Bugl et al. Blood 2013). In contrast, emergency granulopoiesis was shown to be dependent on MyD88 signaling in endothelial cells (Boettcher et al. Blood 2014). Bone marrow mesenchymal stromal cells (MSC) are niche-forming cells, harboring and regulating hematopoiesis. Upon steady-state neutropenia an increase of niche size was observed. Here we investigated, whether niche-forming MSC act as sensors of pathogen-associated molecular patterns (PAMPs) and induce granulopoietic cytokines to stimulate expansion of adjacent hematopoietic stem and progenitor cells. MSC of C57BL/6 and TLR4-KO mice were cultured in vitro and treated with LPS for 24 hours. Cells were harvested and qRT-PCR for G-CSF, TLR4, MyD88, TRIF, GM-CSF, IL-1β, IL-18 and Casp-1 was performed After treatment with LPS, RNA of granulopoietic cytokines G-CSF and GM-CSF were massively up regulated in MSC of WT mice. Upstream regulating, inflammasome components IL-1ß and caspase-1 RNA levels increased as well, with little changes in IL-18, TLR4, MyD88 and TRIF. Unexpectedly, TLR4-KO MSC up regulated transcription of IL-1β and G-CSF upon LPS stimulation as well, and caspase-1 was found to be strongly up-regulated in unstimulated TLR4-KO compared to WT MSC. In summary, bone marrow stromal cells are found to be PAMP-sensing and secrete cytokines that regulate granulopoiesis. TLR4-independent sensing of LPS by MSC might correspond to the alternative noncanonical inflammasome pathway recently described (Kayagaki et al. Science 2013). Disclosures No relevant conflicts of interest to declare.

Murine Hematopoietic Progenitor Cells With Colony-Forming or Radioprotective Capacity Lack Expression of the β2-Integrin LFA-1

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 107-112 ◽  
Author(s):  
Johannes F.M. Pruijt ◽  
Yvette van Kooyk ◽  
Carl G. Figdor ◽  
Roel Willemze ◽  
Willem E. Fibbe
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Progenitor Cells ◽  
Mononuclear Cells ◽  
Hematopoietic Progenitor Cells ◽  
Colony Stimulating Factor ◽  
Hematopoietic Progenitor ◽  
Β2 Integrin ◽  
Stimulating Factor

Abstract Recently, we have demonstrated that antibodies that block the function of the β2-integrin leukocyte function-associated antigen-1 (LFA-1) completely abrogate the rapid mobilization of hematopoietic progenitor cells (HPC) with colony-forming and radioprotective capacity induced by interleukin-8 (IL-8) in mice. These findings suggested a direct inhibitory effect of these antibodies on LFA-1–mediated transmigration of stem cells through the bone marrow endothelium. Therefore, we studied the expression and functional role of LFA-1 on murine HPC in vitro and in vivo. In steady state bone marrow ± 50% of the mononuclear cells (MNC) were LFA-1neg. Cultures of sorted cells, supplemented with granulocyte colony-stimulating factor (G-CSF)/granulocyte-macrophage colony-stimulating factor (GM-CSF)/IL-1/IL-3/IL-6/stem cell factor (SCF) and erythropoietin (EPO) indicated that the LFA-1neg fraction contained the majority of the colony-forming cells (CFCs) (LFA-1neg 183 ± 62/7,500 cells v LFA-1pos 29 ± 17/7,500 cells,P &lt; .001). We found that the radioprotective capacity resided almost exclusively in the LFA-1neg cell fraction, the radioprotection rate after transplantation of 103, 3 × 103, 104, and 3 × 104 cells being 63%, 90%, 100%, and 100% respectively. Hardly any radioprotection was obtained from LFA-1pos cells. Similarly, in cytokine (IL-8 and G-CSF)–mobilized blood, the LFA-1neg fraction, which comprised 5% to 10% of the MNC, contained the majority of the colony-forming cells, as well as almost all cells with radioprotective capacity. Subsequently, primitive bone marrow-derived HPC, represented by Wheat-germ-agglutinin (WGA)+/Lineage (Lin)−/Rhodamine (Rho)− sorted cells, were examined. More than 95% of the Rho− cells were LFA-1neg. Cultures of sorted cells showed that the LFA-1neg fraction contained all CFU. Transplantation of 150 Rho− LFA-1neg or up to 600 Rho−LFA-1pos cells protected 100% and 0% of lethally irradiated recipient mice, respectively. These results show that primitive murine HPC in steady-state bone marrow and of cytokine-mobilized blood do not express LFA-1.

Laminin α4 Deficiency Results in Impaired Hematopoietic Recovery Accompanied with Altered Bone Marrow Niche after Myelosuppression

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 27-27
Author(s):  
Makoto Kondo ◽  
Pingnan Xiao ◽  
Lakshmi Sandhow ◽  
Monika Dolinska ◽  
Thibault Bouderlique ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Steady State ◽  
Progenitor Cells ◽  
Wild Type ◽  
Post Irradiation ◽  
Colony Forming Unit ◽  
Hematopoietic Recovery

Abstract Myelosuppression is a life-threatening complication of anti-cancer therapy including irradiation. Rapid and complete hematopoietic recovery after therapy-induced myelosuppression is required for a successful treatment outcome. This process relies on efficient regeneration of hematopoietic stem cells (HSCs) and is tightly controlled by bone marrow (BM) microenvironment consisting of mesenchymal stem/progenitor cells, endothelial cells as well as secreted factors including cytokines and extracellular matrix proteins (ECM). However, the extrinsic factors critical for promoting the hematopoietic recovery remain poorly understood. Laminins are heterotrimetric ECM composed of α, β, and γ chains. Laminin α4 chain (LAMA4) is an active component for laminin-411 and -421, which are located in vascular basement membrane. LAMA4 plays an important role for HSC homing after transplantation via interaction with laminin receptor integrin α6 (Qian H et al., Blood 2006). However, the role of LAMA4 in normal hematopoiesis and HSC reconstitution after irradiation-induced myelosuppression is not known. In this study, we first detected Lama4 gene expression in BM endothelial cells (CD31+), mesenchymal stem cells (MSC: CD45-Ter119-CD31-CD44-Sca1+CD51+), and mesenchymal progenitor cells (MPC: CD45-Ter119-CD31-CD44-Sca1-CD51+) in young adult mice. By using Lama4 deficient (Lama4-/-) mice, we analyzed the functional role of LAMA4 on hematopoietic activity at steady state. We found the lower number of platelets (PLTs) (p = 0.03), and neutrophils (Gr1+CD11b+) (p = 0.03) in the peripheral blood (PB) of Lama4-/- mice, but a higher frequency of common myeloid progenitor (Lin-Sca1-Kit+CD34+FcRlow) (p < 0.01) in the Lama4-/- BM at steady state, indicating that LAMA4 plays a role in the maintenance of physiological hematopoiesis. The important role of LAMA4 in hematopoietic recovery was demonstrated by delayed and incomplete recoveries of mature red blood cells, PLTs, and Gr1+CD11b+ cells in PB following sublethal irradiation (7Gy). The impaired recovery of erythropoiesis was also indicated by the higher values of mean corpuscular hemoglobin and mean corpuscular volume in PB as well as the higher frequency of megakaryocyte-erythrocyte progenitor (Lin-Sca1-Kit+CD34-FcR-) (p < 0.01) and colony-forming unit-erythrocyte (CFU-E) (p = 0.03) in the BM of the Lama4-/- mice at 6 weeks after irradiation, suggesting blocked erythrocyte maturation. In keeping with the refractory neutropenia, the frequency of colony-forming unit-granulocyte-macrophage (CFU-GM) was lower in the Lama4-/- BM compared to that in the age- and gender-matched wild type mice (p = 0.04). These data indicate that LAMA4 is critical for multiple hematopoietic lineage reconstitution post irradiation. To investigate the cellular and molecular mechanisms underlying the critical role of LAMA4 in hematopoietic recovery after the irradiation, we characterized the BM niche by colony assay, flow cytometry immunophenotyping, quantitative real time PCR (qPCR), and histological analysis. The number of colony-forming unit-fibroblast (CFU-F) was comparable between wild type and Lama4-/- in steady state. Interestingly, the proportion of BM MPCs, a population containing osteoblast progenitors, was significantly lower in the Lama4-/- mice compared to that in the wild type controls at steady state (p < 0.01). qPCR analysis showed downregulation of Il6 (p < 0.05) in the MSC and Angpt1 (p = 0.02) in the MPC of the Lama4-/-mice post irradiation. These data suggest that Lama4 deficiency alters BM stromal cell composition and gene expressions, which may be related to the impaired hematopoietic reconstitution. The recovery of BM vascular structure is essential for efficient reconstitution of hematopoiesis. We observed uniquely dilated blood vessels in Lama4-/- BM at 6-week post irradiation. This might be caused by the lower Angpt1 expression in Lama4-/- MPC since Angpt1/Tie2 signaling is required for vascular regeneration (Kopp HG et al., Blood 2005, Zhou BO et al., eLife 2015). The functional consequences of this phenotype are still under investigation. Altogether, LAMA4 is required for rapid and complete hematopoietic recovery post irradiation-induced myelosuppression. Therapeutic strategies to upregulate Lama4 may facilitate the recovery of hematopoiesis following HSC transplantation under preconditioning using irradiation. Disclosures No relevant conflicts of interest to declare.

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