scholarly journals Maintenance of the BMP4-dependent stress erythropoiesis pathway in the murine spleen requires hedgehog signaling

Blood ◽  
2009 ◽  
Vol 113 (4) ◽  
pp. 911-918 ◽  
Author(s):  
John M. Perry ◽  
Omid F. Harandi ◽  
Prashanth Porayette ◽  
Shailaja Hegde ◽  
Arun K. Kannan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell Factor ◽  
Hedgehog Signaling ◽  
Bone Marrow Cells ◽  
Erythroid Progenitors ◽  
Acute Anemia ◽  
Stress Erythropoiesis ◽  
Murine Spleen ◽  
Stress Response Pathway ◽  
Specialized Population

Abstract The production of mature cells necessitates that lineage-committed progenitor cells be constantly generated from multipotential progenitors. In addition, the ability to respond rapidly to physiologic stresses requires that the signals that regulate the maintenance of progenitor populations be coordinated with the signals that promote differentiation of progenitors. Here we examine the signals that are necessary for the maintenance of the BMP4-dependent stress erythropoiesis pathway. Our previous work demonstrated that BMP4, stem cell factor, and hypoxia act in concert to promote the expansion of a specialized population of stress erythroid progenitors in the spleen during the recovery from acute anemia. Our analysis shows that acute anemia leads to an almost complete mobilization of BMP4-responsive stress erythroid burst-forming units; therefore, new stress progenitors must be recruited to the spleen to replenish this system. We show that bone marrow cells can home to the spleen and, in response to a signal in the spleen microenvironment, Hedgehog, they develop into BMP4-responsive stress progenitors. Hedgehog induces the expression of BMP4, and together these 2 signals are required for the development of BMP4-responsive stress progenitors. These data demonstrate that the interplay between these 2 signals is crucial for maintenance of this stress response pathway.

BMP4/Madh5 Dependent Signaling Is Required for the Expansion of a Population of Stress Erythroid Progenitors in the Fetal Liver.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4195-4195
Author(s):  
Robert F. Paulson ◽  
Prashanth Porayette
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Fetal Liver ◽  
Erythroid Progenitors ◽  
Acute Anemia ◽  
Erythroid Response ◽  
Stress Erythropoiesis ◽  
And Control ◽  
Flexed Tail

Abstract Fetal liver hematopoiesis is primarily erythropoiesis, which robustly produces erythrocytes to meet the growing need of the developing embryo. In many ways fetal liver erythropoiesis resembles stress erythropoiesis in the adult, where in response to acute anemia, a unique population of stress erythroid progenitors is rapidly expanded in the spleen. The development of these stress progenitors requires BMP4/Madh5 dependent signals. Spleen stress progenitors exhibit properties that are distinct from bone marrow steady state progenitors in that they are able to rapidly form large BFU-E colonies, which require only Epo stimulation for their generation. Mice mutant at the flexed-tail locus exhibit a defective stress erythroid response because of a mutation in Madh5. In addition to this defect, flexed-tail mice also exhibit a severe fetal-neonatal anemia. We have analyzed fetal liver erythropoiesis in flexed-tail and control embryos. We show that BMP4 is expressed in the fetal liver and its expression correlates with the time of maximum erythropoiesis. In flexed-tail mutant embryos the expression is delayed and this correlates with both a delay and a defect in the expansion of erythroid progenitors. Our analysis also shows that the fetal liver contains two types of erythroid progenitors. One type exhibits the properties of stress BFU-E found in the adult spleen, which are compromised in flexed-tail embryos and a second type that is similar to bone marrow steady state BFU-E. These data demonstrate that BMP4 dependent signaling drives the expansion of erythroid progenitors in the fetal liver in a manner similar to stress erythropoiesis in the adult spleen.

Erythropoietin Injections Stimulate Spleen BMP4-Dependant Stress Erythropoiesis in a Mouse Model of Generalized Inflammation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1983-1983
Author(s):  
Sarah Millot ◽  
Valerie Andrieu ◽  
Philippe Letteron ◽  
Sigismond Lasocki ◽  
Carole Beaumont
Keyword(s):  
Bone Marrow ◽  
Mouse Model ◽  
Stromal Cells ◽  
Rapid Expansion ◽  
Strong Increase ◽  
Erythroid Progenitors ◽  
Acute Anemia ◽  
Stress Erythropoiesis ◽  
Bmp4 Expression ◽  
Erythropoietic Response

Abstract Abstract 1983 Poster Board I-1005 Introduction: In mouse, acute anemia leads to the rapid expansion and differentiation of stress erythroid progenitors in the spleen. It has been shown that these progenitors respond to BMP4, Stem Cell Factor and hypoxia and differentiate into stress BFU-E. These are sensitive to high levels of erythropoietin (EPO) and rapidly expand in the spleen, allowing rapid recovery from the anemia (JM Perry et al., Blood 2009, 113:911-918). Inflammation is known to inhibit growth and differentiation of erythroid progenitors and to suppress EPO synthesis in the kidney. However, the effect of pro-inflammatory cytokines on this stress erythropoiesis response is not known. We have recently developed a mouse model of zymosan-induced generalized inflammation and shown that stimulation of erythropoiesis by repeated blood withdrawal or injections of erythropoietin favours iron mobilization from tissue iron stores (S. Lasocki et al., CCM 2008, 36:2388-2394), suggesting that EPO treatment may be beneficial provided effective erythropoiesis can be elicited. Objectives: The aim of our study was to assess the impact of EPO injections on the stress erythropoietic response in this mouse model of chronic inflammation. Methods: Mice (C57BL/6) received a single intraperitoneal injection of zymosan at day 1 (Z1) followed by four consecutive daily injections of EPO at day 5, 6, 7 and 8. Mice were analyzed one day (Z9EPO1), four days (Z12EPO4) or nine days (Z17EPO9) after the final injection and compared to controls, Z alone or EPO alone. Double Ter119/CD71 labelling was used to analyze the different stages of erythroblast differentiation by FACS, in bone marrow and spleen in the different conditions. Spleen BMP4 expression was followed by RT-qPCR and immunohistochemistry. Serum EPO levels were measured by ELISA and haematological parameters were recorded. Results: In the inflammatory condition, bone marrow erythropoiesis is suppressed and does not respond to EPO injections. There is a concomitant increased in the percentage of apoptotic Ter119+ cells. In the spleen, inflammation increases spleen size but only moderately stimulates the percentage of erythroblasts. However, EPO injections lead to a 10-fold increase in the percentage of immature erythroblasts at Z9EPO1, followed three days later (Z12EPO4) by a similar increase in the proportion of mature erythroblasts. This finally results in increased reticulocytes and haemoglobin concentration. In the spleen, BMP4 mRNAs are not stimulated by inflammation but significantly increased by EPO injections, both in normal mice and mice with Zymosan-induced inflammation. The protein BMP4 is expressed by erythroid precursors and stromal cells. Double labelling with F4/80 and BMP4 clearly shows that spleen macrophages are the BMP4-expressing cells following EPO injections in mice with a generalized inflammation. Conclusion: In mouse, bone marrow erythropoiesis is repressed by inflammation as it has been shown for human erythropoiesis and it does not respond to EPO injections. By contrast, spleen stress erythropoiesis is strongly stimulated by injections of EPO despite the presence of inflammation. This results from a strong increase in BMP4 synthesis by spleen macrophages. BMP4 is known to be stimulated by acute anemia but our study is the first report of a direct effect of EPO injections on BMP4 expression in the spleen and of the identification of macrophages as the stromal cells producing BMP4. It will be of interest to find out if bone marrow macrophages in humans can synthesize BMP4 and also contribute to a medullar stress erythropoietic response. Disclosures: No relevant conflicts of interest to declare.

The MAPK ERK1 is a negative regulator of the adult steady-state splenic erythropoiesis

Blood ◽  
2010 ◽  
Vol 115 (18) ◽  
pp. 3686-3694 ◽  
Author(s):  
Soizic Guihard ◽  
Denis Clay ◽  
Laurence Cocault ◽  
Nathalie Saulnier ◽  
Paule Opolon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Bone Marrow Cells ◽  
Serum Levels ◽  
Negative Regulator ◽  
Erythroid Progenitors ◽  
Stress Erythropoiesis ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Abstract The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 1 (ERK1) and ERK2 are among the main signal transduction molecules, but little is known about their isoform-specific functions in vivo. We have examined the role of ERK1 in adult hematopoiesis with ERK1−/− mice. Loss of ERK1 resulted in an enhanced splenic erythropoiesis, characterized by an accumulation of erythroid progenitors in the spleen, without any effect on the other lineages or on bone marrow erythropoiesis. This result suggests that the ablation of ERK1 induces a splenic stress erythropoiesis phenotype. However, the mice display no anemia. Deletion of ERK1 did not affect erythropoietin (EPO) serum levels or EPO/EPO receptor signaling and was not compensated by ERK2. Splenic stress erythropoiesis response has been shown to require bone morphogenetic protein 4 (BMP4)–dependent signaling in vivo and to rely on the expansion of a resident specialized population of erythroid progenitors, termed stress erythroid burst-forming units (BFU-Es). A great expansion of stress BFU-Es and increased levels of BMP4 mRNA were found in ERK1−/− spleens. The ERK1−/− phenotype can be transferred by bone marrow cells. These findings show that ERK1 controls a BMP4-dependent step, regulating the steady state of splenic erythropoiesis.

Hedgehog Signaling Molecules in Bone Marrow Cells at the Initial Stage of Fracture Repair

1999 ◽  
Vol 262 (2) ◽  
pp. 443-451 ◽  
Author(s):  
Hiromu Ito ◽  
Haruhiko Akiyama ◽  
Chohei Shigeno ◽  
Ken-ichi Iyama ◽  
Hideaki Matsuoka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hedgehog Signaling ◽  
Bone Marrow Cells ◽  
Signaling Molecules ◽  
Fracture Repair ◽  
Initial Stage ◽  
Marrow Cells

scholarly journals Total marrow failure induced by pegylated stem-cell factor administered before 5-fluorouracil

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3491-3499 ◽  
Author(s):  
G Molineux ◽  
A Migdalska ◽  
J Haley ◽  
GS Evans ◽  
TM Dexter
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Factor ◽  
Transforming Growth Factor ◽  
Bone Marrow Cells ◽  
Drug Dose ◽  
Tgf Beta ◽  
Concurrent Administration ◽  
Sensitizing Effect ◽  
Marrow Cells

Abstract To examine the potential role of stem-cell factor (SCF) in cancer chemotherapy, we have administered it to mice either before or after 5- fluorouracil (5-FU). When polyethylene glycolated (PEG-ylated) SCF was administered to mice before 5-FU, it had a significant sensitizing effect on primitive bone marrow cells. Examination of the hematopoietic status of these mice showed that the damage caused by 5-FU to both bone marrow and spleen hematopoiesis was exaggerated when it was preceded by SCF. SCF given before each of two 5-FU treatments at 7-day intervals resulted in the death of all treated mice. The time of death and hematopoietic status of these animals are compatible with the onset of hypoplastic marrow failure leading to pancytopenia and death. SCF given after 5-FU had little impact either on the initial degree of hematopoietic damage or subsequent recovery. Gut populations were similarly sensitized to 5-FU by prior treatment with SCF, and the damage caused to intestinal populations was greater than that resulting from 5-FU alone. This indicates that the different tissues may be similarly sensitized by SCF. The sensitizing effect of SCF was reversed by concurrent administration of transforming growth factor (TGF)-beta 3, and survival of the majority of the mice was ensured. Examination of hematopoiesis in mice treated concurrently with SCF and TGF-beta 3 showed that the degree of marrow and spleen damage had reverted to that caused by 5-FU alone. In further experiments, 100% survival and normal hematopoiesis could be attained by transplantation of 1 million syngeneic bone marrow cells 24 hours after 5-FU treatment following SCF sensitization. These data indicate that PEG-ylated SCF can sensitize normally resistant hematopoietic and gut stem cells to the effects of 5- FU. This sensitization resulted in effective eradication of hematopoiesis in SCF-pretreated/5-FU-treated animals and their subsequent death from marrow failure. These findings imply that SCF pretreatment may represent a novel method of increasing the effectiveness of conventional chemotherapy, making marrow ablation more effective without drug dose escalation and perhaps sensitizing some tumor cells to the effects of therapy.

Glycoprotein IIb-IIIa Is Expressed on Avian Multilineage Hematopoietic Progenitor Cells

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 2898-2906 ◽  
Author(s):  
Christiane Ody ◽  
Pierre Vaigot ◽  
Pascale Quéré ◽  
Beat A. Imhof ◽  
Catherine Corbel
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Cell Transfer ◽  
Hematopoietic Progenitors ◽  
Erythroid Progenitors ◽  
Hematopoietic Progenitor ◽  
Hematopoietic System ◽  
Fibrinogen Receptor ◽  
Aortic Area ◽  
Adult Bone

The fibrinogen receptor GPIIb-IIIa integrin is known to be expressed on cells of the megakaryocytic lineage, but its presence on hematopoietic progenitors has been a controversial issue. To resolve this ambiguity unequivocally, we performed clonogenic assays and intrathymic cell-transfer experiments in congenic animals. As the ontogeny of the avian hematopoietic system is well documented, we used this experimental model to trace GPIIb-IIIa expression during embryogenesis. Consequently, we now report that the GPIIb-IIIa integrin is expressed as early as embryonic day 3.5 (E3.5) to 4 in intraaortic hematopoietic clusters, the first site of intraembryonic hematopoietic progenitor emergence, and later in E6 paraaortic foci. Myeloid and erythroid progenitors were also detected within the GPIIb-IIIa+ CD45+ population isolated from the E3.5 to 4 aortic area, while in embryonic and adult bone marrow, myeloid, erythroid, and T-cell progenitors were present in the GPIIb-IIIa+ c-kit+ population. Furthermore, we also provide the first evidence, that GPIIb-IIIa+ bone marrow cells can differentiate into T cells. Hence, GPIIb-IIIa can be used as a marker for multilineage hematopoietic progenitors, permitting identification of early intraembryonic sites of hematopoiesis, as well as the isolation of embryonic and adult hematopoietic progenitors.

MHC class II and c-kit expression allows rapid enrichment of T-cell progenitors from total bone marrow cells

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3988-3990
Author(s):  
Christiane Ody ◽  
Catherine Corbel ◽  
Dominique Dunon ◽  
Olli Vainio ◽  
Beat A. Imhof
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Mhc Class Ii ◽  
Bone Marrow Cells ◽  
Class Ii ◽  
Tyrosine Kinase Receptor ◽  
Erythroid Progenitors ◽  
T Cell Progenitors ◽  
Total Bone Marrow ◽  
Embryonic Bone

T-cell progenitors in the embryonic bone marrow express the tyrosine kinase receptor c-kit. RR5, an anti-MHC class II β chain monoclonal antibody, subdivides this c-kit positive population. Intrathymic transfer experiments showed that most of the T-cell progenitors belong to the MHC class II+/c-kit+ bone marrow population in the embryo and young adult. On transplantation, these bone marrow progenitors lose this expression and differentiate into CD4 CD8 T lymphocytes. In contrast, erythroid progenitors are restricted to the MHC class II−/c-kit+ population. The MHC class II+/c-kit+ pro-T cells are metabolically active, because they stain brightly with rhodamin 123. Their cyclin A and B expression level suggests that they are in the mitotic phase of the cell cycle. Thus, we define an easy sorting protocol, which allows enrichment of T-cell progenitors from total bone marrow hemopoietic cells.

scholarly journals Effect of stem cell factor on in vitro erythropoiesis in patients with bone marrow failure syndromes

Blood ◽  
1992 ◽  
Vol 80 (12) ◽  
pp. 3000-3008
Author(s):  
BP Alter ◽  
ME Knobloch ◽  
L He ◽  
AP Gillio ◽  
RJ O'Reilly ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Factor ◽  
Mononuclear Cells ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Normal Numbers ◽  
Erythroid Progenitors ◽  
Bone Marrow Failure Syndromes

Stem cell factor (SCF) enhances normal hematopoiesis. We examined its effect in vitro on bone marrow and blood progenitors from patients with inherited bone marrow failure syndromes, including 17 patients each with Diamond-Blackfan anemia (DBA) and Fanconi's anemia (FA), 3 with dyskeratosis congenita (DC), and 1 each with amegakaryocytic thrombocytopenia (amega) and transient erythroblastopenia of childhood (TEC). Mononuclear cells were cultured with erythropoietin (Ep) alone or combined with SCF or other factors. SCF increased the growth of erythroid progenitors in cultures from 50% of normal controls, 90% of DBA, 70% of FA, 30% of DC, and the amega and TEC patients; normal numbers were reached in 25% of DBA studies. Improved in vitro erythropoiesis with SCF in all types of inherited marrow failure syndromes does not suggest a common defect involving kit or SCF, but implies that SCF may be helpful in the treatment of hematopoietic defects of varied etiologies.

scholarly journals Induction of mixed erythroid-megakaryocyte colonies and bipotential blast cell colonies by recombinant human erythropoietin in serum-free culture

Blood ◽  
1990 ◽  
Vol 76 (7) ◽  
pp. 1330-1335
Author(s):  
N Nishi ◽  
T Nakahata ◽  
K Koike ◽  
M Takagi ◽  
K Naganuma ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Recombinant Human Erythropoietin ◽  
Bone Marrow Cells ◽  
Blast Cell ◽  
Mouse Bone Marrow ◽  
High Concentration ◽  
Erythroid Progenitors ◽  
Serum Free ◽  
Human Erythropoietin ◽  
Marrow Cells

The effects of recombinant human erythropoietin (rEp) on murine hematopoietic progenitors were studied using a serum-free culture. A high concentration of rEp stimulated the formation of mixed erythroid- megakaryocyte colonies (EM colonies) and blast cell colonies, as well as erythroid colonies, erythroid bursts, and megakaryocyte colonies from normal mouse bone marrow cells. Direct effects of rEp on EM colony, megakaryocyte colony, and erythroid burst formation were confirmed by depletion of accessory cells such as T cells, B cells, and macrophages from crude bone marrow cells, and inhibition of the colonies by the addition of rabbit anti-rEp antibody to the culture in a dose-dependent fashion. Replating experiments were performed to confirm the differentiating ability of blast cell colonies grown in the presence of rEp. Most of the blast cell colonies yielded not only secondary erythroid colonies but also megakaryocyte colonies in the presence of 2 IU/mL rEp. Some of the blast cell colonies produced secondary EM colonies in the presence of 16 IU/ml rEp of 2 IU/mL rEp plus interleukin-3, although no granulocyte-macrophage colonies were found in the secondary culture. These results suggest that Ep acts not only as a late-acting factor that is specific for erythroid progenitors, but also as a bipotential EM-stimulating factor for murine hematopoietic cells.

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