scholarly journals In vivo hematopoietic effects of recombinant interleukin-1 alpha in mice: stimulation of granulocytic, monocytic, megakaryocytic, and early erythroid progenitors, suppression of late-stage erythropoiesis, and reversal of erythroid suppression with erythropoietin

Blood ◽  
1989 ◽  
Vol 73 (3) ◽  
pp. 678-683
Author(s):  
CS Johnson ◽  
DJ Keckler ◽  
MI Topper ◽  
PG Braunschweiger ◽  
P Furmanski
Keyword(s):  
Progenitor Cells ◽  
Late Stage ◽  
Peripheral Blood ◽  
Interleukin 1 ◽  
Post Treatment ◽  
Erythroid Progenitors ◽  
In Vivo Effects ◽  
Potential Use

Interleukin-1 alpha (IL-1 alpha) is a macrophage-derived, multifunctional cytokine that broadly potentiates myelopoiesis and induces the synthesis of hematopoietic colony-stimulating factors (CSF) in vitro and in vivo. To evaluate the possibility for use of IL-1 alpha in ameliorating in vivo bone marrow suppression induced by drugs or radiation, we examined the in vivo effects of the cytokine on erythropoietic and other hematopoietic progenitor cells. Normal mice were treated with a single intraperitoneal (IP) injection of recombinant human IL-1 alpha at varying doses and were assayed at various times post-treatment. By six hours postinjection, a significant suppression of mature erythroid progenitors (CFU-E) was observed in animals treated with IL-1 alpha (0.5 micrograms/mouse), with maximum suppression of CFU-E and peripheral blood reticulocyte counts occurring at 24 hours. Decreases in peripheral blood hematocrit did not occur after a single IL-1 alpha injection but were observed after multiple injections of the cytokine. The suppressive effects of IL-1 alpha on late-stage erythropoiesis were abrogated by simultaneous administration of erythropoietin (EPO). At 48 hours post-treatment, a marked stimulation was observed in the numbers of spleen and marrow immature erythroid (BFU-E), macrophage (CFU-M), granulocyte (CFU-G), granulocyte- macrophage (CFU-GM), and megakaryocyte (CFU-meg) progenitor cells. These results demonstrate the potential use of IL-1 alpha as a generalized stimulator of hematopoiesis and show that the cytokine- induced suppression of late-stage erythropoiesis can be prevented by EPO.

scholarly journals In vivo hematopoietic effects of recombinant interleukin-1 alpha in mice: stimulation of granulocytic, monocytic, megakaryocytic, and early erythroid progenitors, suppression of late-stage erythropoiesis, and reversal of erythroid suppression with erythropoietin

Blood ◽  
1989 ◽  
Vol 73 (3) ◽  
pp. 678-683 ◽  
Author(s):  
CS Johnson ◽  
DJ Keckler ◽  
MI Topper ◽  
PG Braunschweiger ◽  
P Furmanski
Keyword(s):  
Progenitor Cells ◽  
Late Stage ◽  
Peripheral Blood ◽  
Interleukin 1 ◽  
Post Treatment ◽  
Erythroid Progenitors ◽  
In Vivo Effects ◽  
Potential Use

Abstract Interleukin-1 alpha (IL-1 alpha) is a macrophage-derived, multifunctional cytokine that broadly potentiates myelopoiesis and induces the synthesis of hematopoietic colony-stimulating factors (CSF) in vitro and in vivo. To evaluate the possibility for use of IL-1 alpha in ameliorating in vivo bone marrow suppression induced by drugs or radiation, we examined the in vivo effects of the cytokine on erythropoietic and other hematopoietic progenitor cells. Normal mice were treated with a single intraperitoneal (IP) injection of recombinant human IL-1 alpha at varying doses and were assayed at various times post-treatment. By six hours postinjection, a significant suppression of mature erythroid progenitors (CFU-E) was observed in animals treated with IL-1 alpha (0.5 micrograms/mouse), with maximum suppression of CFU-E and peripheral blood reticulocyte counts occurring at 24 hours. Decreases in peripheral blood hematocrit did not occur after a single IL-1 alpha injection but were observed after multiple injections of the cytokine. The suppressive effects of IL-1 alpha on late-stage erythropoiesis were abrogated by simultaneous administration of erythropoietin (EPO). At 48 hours post-treatment, a marked stimulation was observed in the numbers of spleen and marrow immature erythroid (BFU-E), macrophage (CFU-M), granulocyte (CFU-G), granulocyte- macrophage (CFU-GM), and megakaryocyte (CFU-meg) progenitor cells. These results demonstrate the potential use of IL-1 alpha as a generalized stimulator of hematopoiesis and show that the cytokine- induced suppression of late-stage erythropoiesis can be prevented by EPO.

Is the Success of Cefazolin plus Ertapenem in Methicillin-Susceptible Staphylococcus aureus Bacteremia Based on Release of Interleukin 1-beta?

2022 ◽  
Author(s):  
Dan Smelter ◽  
Mary Hayney ◽  
George Sakoulas ◽  
Warren Rose
Keyword(s):  
Staphylococcus Aureus ◽  
Peripheral Blood ◽  
Interleukin 1 ◽  
Interleukin 1 Beta ◽  
Blood Monocytes ◽  
Salvage Regimen ◽  
Peripheral Blood Monocytes ◽  
Staphylococcus Aureus Bacteremia

Cefazolin and ertapenem has been shown to be an effective salvage regimen for refractory methicillin-susceptible Staphylococcus aureus bacteremia. Our findings suggest cefazolin plus ertapenem in vitro stimulates interleukin-1β release from peripheral blood monocytes both with and without S. aureus presence. This IL-1β augmentation was primarily driven by ertapenem. These findings support further exploration of cefazolin plus ertapenem in MSSA bacteremia and may partially explain its marked potency in vivo despite modest synergy in vitro .

scholarly journals Thrombopoietin, but not erythropoietin promotes viability and inhibits apoptosis of multipotent murine hematopoietic progenitor cells in vitro

Blood ◽  
1996 ◽  
Vol 88 (8) ◽  
pp. 2859-2870 ◽  
Author(s):  
OJ Borge ◽  
V Ramsfjell ◽  
OP Veiby ◽  
MJ Jr Murphy ◽  
S Lok ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Interleukin 1 ◽  
Calf Serum ◽  
Myeloid Cell ◽  
Promoting Effect ◽  
Multipotent Progenitors

The recently cloned c-mpl ligand, thrombopoietin (Tpo), has been extensively characterized with regard to its ability to stimulate the growth, development, and ploidy of megakaryocyte progenitor cells and platelet production in vitro and in vivo. Primitive hematopoietic progenitors have been shown to express c-mpl, the receptor for Tpo. In the present study, we show that Tpo efficiently promotes the viability of a subpopulation of Lin-Sca-1+ bone marrow progenitor cells. The ability of Tpo to maintain viable Lin-Sca-1+ progenitors was comparable to that of granulocyte colony-stimulating factor and interleukin-1, whereas stem cell factor (SCF) promoted the viability of a higher number of Lin-Sca-1+ progenitor cells when incubated for 40 hours. However, after prolonged (> 40 hours) preincubation, the viability-promoting effect of Tpo was similar to that of SCF. An increased number of progenitors surviving in response to Tpo had megakaryocyte potential (37%), although almost all of the progenitors produced other myeloid cell lineages as well, suggesting that Tpo acts to promote the viability of multipotent progenitors. The ability of Tpo to promote viability of Lin-Sca-1+ progenitor cells was observed when cells were plated at a concentration of 1 cell per well in fetal calf serum-supplemented and serum-depleted medium. Finally, the DNA strand breakage elongation assay showed that Tpo inhibits apoptosis of Lin-Sca-1+ bone marrow cells. Thus, Tpo has a potent ability to promote the viability and suppress apoptosis of primitive multipotent progenitor cells.

Novel In Vivo Evidence That Not Only Androgens But Also Pituitary Gonadotropins and Prolactin Directly Stimulate Murine Bone Marrow Stem Cells – Implications For Potential Treatment Strategies In Aplastic Anemias

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2476-2476
Author(s):  
Kasia Mierzejewska ◽  
Ewa Suszynska ◽  
Sylwia Borkowska ◽  
Malwina Suszynska ◽  
Maja Maj ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Sex Hormones ◽  
Peripheral Blood ◽  
Hematopoietic Stem ◽  
Clonogenic Potential

Abstract Background Hematopoietic stem/progenitor cells (HSPCs) are exposed in vivo to several growth factors, cytokines, chemokines, and bioactive lipids in bone marrow (BM) in addition to various sex hormones circulating in peripheral blood (PB). It is known that androgen hormones (e.g., danazol) is employed in the clinic to treat aplastic anemia patients. However, the exact mechanism of action of sex hormones secreted by the pituitary gland or gonads is not well understood. Therefore, we performed a complex series of experiments to address the influence of pregnant mare serum gonadotropin (PMSG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), androgen (danazol) and prolactin (PRL) on murine hematopoiesis. In particular, from a mechanistic view we were interested in whether this effect depends on stimulation of BM-residing stem cells or is mediated through the BM microenvironment. Materials and Methods To address this issue, normal 2-month-old C57Bl6 mice were exposed or not to daily injections of PMSG (10 IU/mice/10 days), LH (5 IU/mice/10 days), FSH (5 IU/mice/10 days), danazol (4 mg/kg/10 days) and PRL (1 mg/day/5days). Subsequently, we evaluated changes in the BM number of Sca-1+Lin–CD45– that are precursors of long term repopulating hematopoietic stem cells (LT-HSCs) (Leukemia 2011;25:1278–1285) and bone forming mesenchymal stem cells (Stem Cell & Dev. 2013;22:622-30) and Sca-1+Lin–CD45+ hematopoietic stem/progenitor cells (HSPC) cells by FACS, the number of clonogenic progenitors from all hematopoietic lineages, and changes in peripheral blood (PB) counts. In some of the experiments, mice were exposed to bromodeoxyuridine (BrdU) to evaluate whether sex hormones affect stem cell cycling. By employing RT-PCR, we also evaluated the expression of cell-surface and intracellular receptors for hormones in purified populations of murine BM stem cells. In parallel, we studied whether stimulation by sex hormones activates major signaling pathways (MAPKp42/44 and AKT) in HSPCs and evaluated the effect of sex hormones on the clonogenic potential of murine CFU-Mix, BFU-E, CFU-GM, and CFU-Meg in vitro. We also sublethally irradiated mice and studied whether administration of sex hormones accelerates recovery of peripheral blood parameters. Finally, we determined the influence of sex hormones on the motility of stem cells in direct chemotaxis assays as well as in direct in vivo stem cell mobilization studies. Results We found that 10-day administration of each of the sex hormones evaluated in this study directly stimulated expansion of HSPCs in BM, as measured by an increase in the number of these cells in BM (∼2–3x), and enhanced BrdU incorporation (the percentage of quiescent BrdU+Sca-1+Lin–CD45– cells increased from ∼2% to ∼15–35% and the percentage of BrdU+Sca-1+Lin–CD45+ cells increased from 24% to 43–58%, Figure 1). These increases paralleled an increase in the number of clonogenic progenitors in BM (∼2–3x). We also observed that murine Sca-1+Lin–CD45– and Sca-1+Lin–CD45+ cells express sex hormone receptors and respond by phosphorylation of MAPKp42/44 and AKT in response to exposure to PSMG, LH, FSH, danazol and PRL. We also observed that administration of sex hormones accelerated the recovery of PB cell counts in sublethally irradiated mice and slightly mobilized HSPCs into PB. Finally, in direct in vitro clonogenic experiments on purified murine SKL cells, we observed a stimulatory effect of sex hormones on clonogenic potential in the order: CFU-Mix > BFU-E > CFU-Meg > CFU-GM. Conclusions Our data indicate for the first time that not only danazol but also several pituitary-secreted sex hormones directly stimulate the expansion of stem cells in BM. This effect seems to be direct, as precursors of LT-HSCs and HSPCs express all the receptors for these hormones and respond to stimulation by phosphorylation of intracellular pathways involved in cell proliferation. These hormones also directly stimulated in vitro proliferation of purified HSPCs. In conclusion, our studies support the possibility that not only danazol but also several other upstream pituitary sex hormones could be employed to treat aplastic disorders and irradiation syndromes. Further dose- and time-optimizing mouse studies and studies with human cells are in progress in our laboratories. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Biology of COP Cells: Mesenchymal of Hematopoietic?

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 45-45
Author(s):  
Meghan McGee-Lawrence
Keyword(s):  
Stem Cells ◽  
Clinical Practice ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Biological Characterization ◽  
Differentiation Capacity ◽  
Growing Body

Abstract Circulating osteogenic precursor (COP) cells constitute a recently discovered population of circulating progenitor cells with the capacity to form not only bone but other mesenchymal tissues. A small but growing body of literature explores these cells, but with a great deal of disagreement and contradiction within it, mainly whether these cells are from mesenchymal or hematopoietic origin. This session will discuss the origins and biological characterization of these cells, including the identification strategies used to isolate these cells from the peripheral blood. It also examines the available knowledge on the in vitro and in vivo behaviour of these cells in plastic adherence, differentiation capacity, proliferation, and cellular homing. We will also review the profound and exciting implications for future use of COP cells in clinical practice, particularly in comparison with other types of stem cells.

scholarly journals IL-33 promotes anemia during chronic inflammation by inhibiting differentiation of erythroid progenitors

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
James W. Swann ◽  
Lada A. Koneva ◽  
Daniel Regan-Komito ◽  
Stephen N. Sansom ◽  
Fiona Powrie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Chronic Inflammation ◽  
Inflammatory Disease ◽  
Erythropoietin Receptor ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

An important comorbidity of chronic inflammation is anemia, which may be related to dysregulated activity of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM). Among HSPCs, we found that the receptor for IL-33, ST2, is expressed preferentially and highly on erythroid progenitors. Induction of inflammatory spondyloarthritis in mice increased IL-33 in BM plasma, and IL-33 was required for inflammation-dependent suppression of erythropoiesis in BM. Conversely, administration of IL-33 in healthy mice suppressed erythropoiesis, decreased hemoglobin expression, and caused anemia. Using purified erythroid progenitors in vitro, we show that IL-33 directly inhibited terminal maturation. This effect was dependent on NF-κB activation and associated with altered signaling events downstream of the erythropoietin receptor. Accordingly, IL-33 also suppressed erythropoietin-accelerated erythropoiesis in vivo. These results reveal a role for IL-33 in pathogenesis of anemia during inflammatory disease and define a new target for its treatment.

scholarly journals Factor-independent erythropoietic progenitor cells in leukemia induced by the myeloproliferative leukemia virus

Blood ◽  
1989 ◽  
Vol 73 (5) ◽  
pp. 1161-1167 ◽  
Author(s):  
F Wendling ◽  
JF Penciolelli ◽  
M Charon ◽  
P Tambourin
Keyword(s):  
Progenitor Cells ◽  
Leukemia Virus ◽  
Erythroid Progenitor ◽  
Adult Mice ◽  
Cell Compartments ◽  
Erythroid Progenitor Cells ◽  
Semi Solid ◽  
In Vivo Effects

Abstract The myeloproliferative leukemia virus (MPLV), a novel murine retroviral complex that does not transform fibroblasts, has been shown to cause an acute leukemia in adult mice accompanied by a progressive polycythemia. The present study demonstrates that, on in vivo inoculation, MPLV induces a rapid suppression of growth factor requirement for in vitro colony formation by both the late and the primitive erythroid progenitor cells. CFU-e-derived erythrocytic colonies developed and differentiated in semi-solid medium without the addition of erythropoietin (Epo). In addition, the formation of CFU-e colonies was not altered by the presence of specific neutralizing Epo antibodies. In the spleen, the CFU-e pool size increased rapidly up to 30-fold. By day 6 postinfection, 100% of these progenitor cells were Epo-independent. The in vivo effects of MPLV-infection on early erythroid progenitor cell compartments were examined in cultures grown for seven days. The concentration of erythroid progenitor cells was twofold elevated in spleen from MPLV-infected mice. As early as day 4 postinfection, 50% of these progenitors produced fully hemoglobinized colonies in serum-free cultures without the addition of interleukin-3 (IL-3) and Epo. Most spontaneous colonies were large and contained up to 10(5) cells per colony. They were composed of either erythroblasts only (16%) or erythroblasts and megakaryocytes (70%); few of them were multipotential (14%). In the marrow, the total number of BFU-e was reduced and only few factor-independent bursts were observed, suggesting a rapid migration of infected progenitors from marrow to spleen. Furthermore, the data show that abnormal erythropoiesis was due to the replication defective MPLV information and was not influenced by the Fv-2 locus.

scholarly journals The Chemokine SDF-1 Is a Chemoattractant for Human CD34+ Hematopoietic Progenitor Cells and Provides a New Mechanism to Explain the Mobilization of CD34+ Progenitors to Peripheral Blood

1997 ◽  
Vol 185 (1) ◽  
pp. 111-120 ◽  
Author(s):  
A. Aiuti ◽  
I.J. Webb ◽  
C. Bleul ◽  
T. Springer ◽  
J.C. Gutierrez-Ramos
Keyword(s):  
Progenitor Cells ◽  
Peripheral Blood ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
Stromal Cell Derived Factor ◽  
Transient Elevation

Hematopoietic progenitor cells migrate in vitro and in vivo towards a gradient of the chemotactic factor stromal cell-derived factor-1 (SDF-1) produced by stromal cells. This is the first chemoattractant reported for human CD34+ progenitor cells. Concentrations of SDF-1 that elicit chemotaxis also induce a transient elevation of cytoplasmic calcium in CD34+ cells. SDF-1-induced chemotaxis is inhibited by pertussis toxin, suggesting that its signaling in CD34+ cells is mediated by seven transmembrane receptors coupled to Gi proteins. CD34+ cells migrating to SDF-1 include cells with a more primitive (CD34+/CD38− or CD34+/DR−) phenotype as well as CD34+ cells phenotypically committed to the erythroid, lymphoid and myeloid lineages, including functional BFU-E, CFU-GM, and CFU-MIX progenitors. Chemotaxis of CD34+ cells in response to SDF-1 is increased by IL-3 in vitro and is lower in CD34+ progenitors from peripheral blood than in CD34+ progenitors from bone marrow, suggesting that an altered response to SDF-1 may be associated with CD34 progenitor mobilization.

scholarly journals Megakaryocytic TGFβ1 Partitions Hematopoiesis into Amplifying Stem and Progenitor Cells and Maturing Effector Cells

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 81-81
Author(s):  
Silvana Di Giandomenico ◽  
Pouneh Kermani ◽  
Nicole Molle ◽  
Mia Yabut ◽  
Fabienne Brenet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Progenitor Cells ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Effector Cells ◽  
Erythroid Precursors ◽  
Stem And Progenitor Cells

Abstract Background: Chronic anemia is a significant problem affecting over 3 million Americans annually. Therapies are restricted to transfusion and Erythropoietin Stimulating Agents (ESA). There is a need for new approaches to treat chronic anemia. Immature erythroid progenitors are thought to be continuously produced and then permitted to survive and mature if there is sufficient erythropoietin (Epo) available. This model is elegant in that oxygen sensing within the kidney triggers Epo production so anemia can increase Epo and promote erythroid output. However, during homeostasis this model suggests that considerable energy is used to produce unneeded erythroid progenitors. We searched for independent control and compartmentalization of erythropoiesis that could couple early hematopoiesis to terminal erythroid commitment and maturation. Methods: We previously found the proportion of bone marrow megakaryocytes (MKs) staining for active, signaling-competent TGFβ transiently increases during bone marrow regeneration after chemotherapy. To assess the functional role of Mk-TGFβ, we crossed murine strains harboring a floxed allele of TGFβ1 (TGFβ1Flox/Flox) littermate with a Mk-specific Cre deleter to generate mice with Mk-specific deletion of TGFβ1 (TGFβ1ΔMk/ΔMk). We analyzed hematopoiesis of these mice using high-dimensional flow cytometry, confocal immunofluorescent microscopy and in vitro and in vivo assays of hematopoietic function (Colony forming assays, and in vivo transplantation). Results: Using validated, 9-color flow cytometry panels capable of quantifying hematopoietic stem cells (HSCs) and six other hematopoietic progenitor populations, we found that Mk-specific deletion of TGFβ1 leads to expansion of immature hematopoietic stem and progenitor cells (HSPCs) (Fig1A&B). Functional assays confirmed a more than three-fold increase in hematopoietic stem cells (HSCs) capable of serially-transplanting syngeneic recipients in the bone marrow (BM) of TGFβ1ΔMk/ΔMk mice compared to their TGFβ1Flox/Flox littermates. Expansion was associated with less quiescent (Go) HSCs implicating Mk-TGFβ in the control of HSC cell cycle entry. Similarly, in vitro colony forming cell assays and in vivo spleen colony forming assays confirmed expansion of functional progenitor cells in TGFβ1ΔMk/ΔMk mice. These results place Mk-TGFβ as a critical regulator of the size of the pool of immature HSPCs. We found that the blood counts and total BM cellularity of TGFβ1ΔMk/ΔMk mice was normal despite the dramatic expansion of immature HSPCs. Using a combination of confocal immunofluorescence microscopy (cleaved caspase 3) (Fig1C) and flow cytometry (Annexin V and cleaved caspase 3) (Fig1D), we found ~10-fold greater apoptosis of mature precursor cells in TGFβ1ΔMk/ΔMk BM and spleens. Coincident with this, we found the number of Epo receptor (EpoR) expressing erythroid precursors to be dramatically increased. Indeed, apoptosis of erythroid precursors peaked as they transitioned from dual positive Kit+EpoR+ precursors to single positive cells expressing EpoR alone. Epo levels were normal in the serum of these mice. We reasoned that the excess, unneeded EpoR+ cells were not supported physiologic Epo levels but might respond to even small doses of exogenous Epo. Indeed, we found that the excess erythroid apoptosis could be rescued by administration of very low doses of Epo (Fig1E). Whereas TGFβ1Flox/Flox mice showed minimal reticulocytosis and no change in blood counts, TGFβ1ΔMk/ΔMk mice responded with exuberant reticulocytosis and raised RBC counts almost 10% within 6 days (Fig. 1F). Low dose Epo also rescued survival of Epo receptor positive erythroid precursors in the bone marrow, spleen and blood of TGFβ1ΔMk/ΔMk mice. TGFβ1ΔMk/ΔMk mice showed a similarly brisk and robust erythropoietic response during recovery from phenylhydrazine-induced hemolysis (Fig.1G). Exogenous TGFβ worsened BM apoptosis and caused anemia in treated mice. Pre-treatment of wild-type mice with a TGFβ signaling inhibitor sensitized mice to low dose Epo. Conclusion: These results place megakaryocytic TGFβ1 as a gate-keeper that restricts the pool of immature HSPCs and couples immature hematopoiesis to the production of mature effector cells. This work promises new therapies for chronic anemias by combining TGFβ inhibitors to increase the outflow of immature progenitors with ESAs to support erythroid maturation. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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