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.

BMP4 and Madh5 regulate the erythroid response to acute anemia

Blood ◽  
2005 ◽  
Vol 105 (7) ◽  
pp. 2741-2748 ◽  
Author(s):  
Laurie E. Lenox ◽  
John M. Perry ◽  
Robert F. Paulson
Keyword(s):  
Steady State ◽  
Mutant Mice ◽  
Systemic Response ◽  
Erythroid Progenitors ◽  
New Model ◽  
Acute Anemia ◽  
Erythroid Response ◽  
Flexed Tail

Abstract Acute anemia initiates a systemic response that results in the rapid mobilization and differentiation of erythroid progenitors in the adult spleen. The flexed-tail (f) mutant mice exhibit normal steady-state erythropoiesis but are unable to rapidly respond to acute erythropoietic stress. Here, we show that f/f mutant mice have a mutation in Madh5. Our analysis shows that BMP4/Madh5-dependent signaling, regulated by hypoxia, initiates the differentiation and expansion of erythroid progenitors in the spleen. These findings suggest a new model where stress erythroid progenitors, resident in the spleen, are poised to respond to changes in the microenvironment induced by acute anemia.

Ablation of Gata1 in adult mice results in aplastic crisis, revealing its essential role in steady-state and stress erythropoiesis

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4375-4385 ◽  
Author(s):  
Laura Gutiérrez ◽  
Saho Tsukamoto ◽  
Mikiko Suzuki ◽  
Harumi Yamamoto-Mukai ◽  
Masayuki Yamamoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Erythroid Progenitors ◽  
Hematopoietic Development ◽  
Stress Erythropoiesis ◽  
Adult Mice ◽  
Aplastic Crisis ◽  
Excessive Proliferation ◽  
Erythropoietic Response

Abstract The transcription factor Gata1 is expressed in several hematopoietic lineages and plays essential roles in normal hematopoietic development during embryonic stages. The lethality of Gata1-null embryos has precluded determination of its role in adult erythropoiesis. Here we have examined the effects of Gata1 loss in adult erythropoiesis using conditional Gata1 knockout mice expressing either interferon- or tamoxifen-inducible Cre recombinase (Mx-Cre and Tx-Cre, respectively). Mx-Cre–mediated Gata1 recombination, although incomplete, resulted in maturation arrest of Gata1-null erythroid cells at the proerythroblast stage, thrombocytopenia, and excessive proliferation of megakaryocytes in the spleen. Tx-Cre–mediated Gata1 recombination resulted in depletion of the erythroid compartment in bone marrow and spleen. Formation of the early and late erythroid progenitors in bone marrow was significantly reduced in the absence of Gata1. Furthermore, on treatment with a hemolytic agent, these mice failed to activate a stress erythropoietic response, despite the rising erythropoietin levels. These results indicate that, in addition to the requirement of Gata1 in adult megakaryopoiesis, Gata1 is necessary for steady-state erythropoiesis and for erythroid expansion in response to anemia. Thus, ablation of Gata1 in adult mice results in a condition resembling aplastic crisis in human.

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.

Defects in Management of Labile Iron and Oxidative Stress Underpin Red Cell Enucleation Defects in Rb Null Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1351-1351
Author(s):  
Kay F. Macleod ◽  
Benjamin T. Spike
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
Steady State ◽  
Fetal Liver ◽  
Red Cells ◽  
Red Cell ◽  
Stress Erythropoiesis ◽  
Labile Iron ◽  
End Stage ◽  
And Oxidative Stress

Abstract The Rb tumor suppressor is critically required for end-stage red cell maturation under conditions of oxidative stress, including in the developing fetal liver, in the bone marrow of aging mice, in the spleen and bone marrow of young mice treated with phenylhydrazine to induce hemolytic anemia, and in lethally irradiated mice reconstituted with donor tissue [1]. Loss of Rb resulted in a failure of end-stage red cells to enucleate, accumulation of red cells with a 4N DNA content and aberrant chromatin structure [1]. The molecular basis of these defects is not defined nor do we understand the reasons why pRb should be required under stress conditions, but not during normal “steady-state” erythropoiesis. The work presented will address both of these questions. In determining why pRb is critically required for stress erythropoiesis but not for steady-state erythropoiesis, we have demonstrated increased levels of reactive oxygen species (ROS) and labile iron in Rb null erythroblasts relative to wild-type control erythroblasts derived from E12.5 fetal liver. Furthermore, we show that quenching of ROS in Rb null erythroblasts by treatment of mice with the anti-oxidant N-acetyl cysteine (NAC) rescued aspects of the erythroid defect, including red cell enucleation and also extended the lifespan of Rb null mice. Similarly, chelation of labile iron with desferroxiamine restored enucleation capacity to Rb null erythroblasts. Furthermore, we show that the transferrin receptor (CD71) is transcriptionally repressed by pRb/E2F and examine whether deregulated expression of CD71 contributes to increased labile iron and oxidative stress in Rb null erythroblasts. These results suggest that loss of pRb limits the ability of erythroblasts to manage labile iron and oxidative stress, in part through deregulated expression of CD71, and that this contributes to the enucleation defect observed in Rb null mice. Given that pRb is itself regulated by ROS, we present a model in which the timely induction and repression of the CD71 receptor in differentiating erythroblasts is required to manage labile iron, oxidative stress and to coordinate cell cycle exit with end-stage maturation.

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.

scholarly journals Complete Spatial Mapping of Steady-State and Stress Erythropoiesis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-7
Author(s):  
Qingqing Wu ◽  
Jizhou Zhang ◽  
Courtney Johnson ◽  
Anastasiya Slaughter ◽  
Margot Lindsay May ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Single Cells ◽  
Differentially Expressed ◽  
Published Data ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Clonal Architecture ◽  
Stress Erythropoiesis

The anatomy of differentiation in the bone marrow (BM) is poorly understood due to lack of markers to image stepwise HSPC differentiation. We analyzed 250+ cell surface molecules in all hematopoietic progenitors and identified 56 differentially expressed markers in at least one HSPC that can be "mixed and matched" to prospectively image any HSPC of interest in the bone marrow. We used this data to develop a pipeline to map stepwise erythropoiesis in vivo. We found that all erythroid progenitors can be defined as Ly6C-CD27-ESAM-CD117+ cells and then Pre-MegE (earliest erythroid progenitor Cell Stem Cell. 2007 1(4):428-42) are CD150+CD71-. These give rise to CD71+CD150+ Pre-CFU-E that differentiate into CD71+CD150- CFU-E that then generate early erythroblasts. All BFU-E activity was restricted to Pre-MegE and Pre- CFU-E (70 and 30% of all BFU-E) whereas all CFU-E colonies were spread between Pre-MegE (44%), pre-CFU-E (10%) and CFU-E (46%). We also confirmed previously published data showing that CD71 and Ter119 can be used to image stepwise terminal erythropoiesis; CD71+Ter119dim early erythroblasts, CD71+Ter119bright late erythroblasts, CD71dimTer119bright reticulocytes and CD71-Ter119bright erythrocytes. Importantly, all populations were detected at identical frequencies using FACS or confocal imaging indicating that our imaging strategy detects all erythroid cells (Pre-CFU-E: 0.022 vs 0.027 %; CFUE: 0.32 vs 0.30%; Early-Ery: 0.62 vs 0.66%; Late-Ery: 32.05 vs 32.12%; Reticulocyte: 5.98 vs. 3.36%; Erythrocytes: 12.49 vs. 13.47%). We mapped the 3D location of every erythroid lineage cell in mouse sternum and interrogated the spatial relationships between the different maturation steps and with candidate niches. We compared the interactions found in vivo with those found in random simulations. Specifically, we used CD45 and Ter119 to obtain the spatial coordinates of every hematopoietic cell. Then we randomly placed each type of erythroid lineage cell at identical frequencies as those found in vivo to generate random simulations. We found erythroid progenitors show no specific association with HSC, indicating that Pre-Meg-E or more primitive progenitors leave the HSC niche after differentiation. Both Pre-Meg-E and Pre-CFU-E are found as single cells through the central BM space and do not specifically associate with other progenitors, or components of the microenvironment. In contrast almost all CFU-E locate to strings (28 strings per sternum) containing 8 CFU-E that are selectively recruited to sinusoids (mean CFU-E to sinusoid distance=2.2µm). As soon as CFU-E detach from sinusoids they downregulate CD117 and upregulate CD71 giving rise to a cluster of early erythroblasts that buds from the vessel. These progressively upregulate Ter119 to generate large clusters of late erythroblasts that in turn differentiate into clusters of reticulocytes and erythrocytes. To examine the clonal architecture of erythropoiesis we used Ubc-creERT2:confetti mice where a tamoxifen pulse leads to irreversible expression of GFP, CFP, YFP or RFP. Four weeks later we found that the CFU-E strings are oligoclonal with each clone contributing 2-6 CFU-E to the string. The budding erythroblasts clusters are similarly organized. These indicate that different CFU-E are serially recruited to the same sinusoidal spot where they self-renew 1-2 times and then undergo terminal differentiation. We then tracked how this architecture changed in response to stress (hemorrhage). Two days after bleeding we found that Pre-Meg-E and Pre-CFU-E numbers and locations were unaltered. The number of CFU-E strings remained constant (30 CFUE strings/sternum) but all strings contained more CFU-E (2-fold) suggesting increased self-renewal. Unexpectedly, fate mapping showed that the size of CFU-E clones did not increase when compared to steady-state. These results indicate that all CFU-E expand in respond to stress and that this is mediated via increased recruitment and differentiation of upstream progenitors. In summary we have found 56 differentially expressed markers that can be combined to detect most HSPC; validated a 5-color stain to image and fate map all steps of red blood cell maturation in situ; demonstrated that terminal erythropoiesis emerges from strings of sinusoidal CFU-E, and revealed the clonal architecture of normal and stress erythropoiesis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Nrf2 Null Mice Are Deficient in CD169+ Macrophages, Associated with Impaired Erythroid Response and Delayed Recovery from Acute Blood Loss

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1038-1038
Author(s):  
Oluwabukola Gbotosho ◽  
Maria G Kapetanaki ◽  
Mark A Ross ◽  
Samit Ghosh ◽  
Frances Weidert ◽  
...  
Keyword(s):  
Steady State ◽  
Blood Loss ◽  
Peripheral Blood ◽  
Research Funding ◽  
Heme Oxygenase 1 ◽  
Acute Blood Loss ◽  
Erythroid Progenitors ◽  
Erythroid Response ◽  
Stress Erythropoiesis ◽  
Deficient Mice

Erythropoiesis occurs in specialized niches in the bone marrow consisting of a central macrophage, surrounded by differentiating erythroblasts. This central macrophage has been identified by several markers including, CD169 (Sialoadhesin or Siglec-1), F4/80, CD11b, VCAM-1, ER-HR3 and Ly-6G. These CD169+ macrophages support erythropoiesis both at steady state and during stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the master regulator of the cellular oxidative defense system. It modulates hematopoietic stem cells but its loss produces no visible phenotype in steady state hematological parameters. However, the importance of Nrf2 and macrophage subsets has not been fully characterized during recovery from stress erythropoiesis. We examined specific subsets of CD169+ macrophage populations in Nrf2 knockout (Nrf2−/−) mice as well as the role of Nrf2 in recovery from stress erythropoiesis in vivo. We quantified the expression of CD169, F4/80 and CD11b, markers of central macrophages, in the BM and spleen of Nrf2+/+ and Nrf2-/- mice at steady state. Surprisingly, Nrf2-/- mice showed a phenotype characterized by lower percentages of cells expressing known macrophage markers. We observed a significant decrease of 47% (p≤0.01), 24% (p≤0.01) and 50% (p≤0.01) in BM macrophage subpopulations expressing F4/80hiCD169hi, F4/80hiCD11bhi and CD169hiCD11bhi respectively, in age-matched Nrf2-/- mice compared to Nrf2+/+ control mice (Fig. 1a). In the spleen, we also observed a similar significant deficiency in BM macrophages (p≤0.01). Further validating this phenotype, immunofluorescence staining of isolated spleen tissue showed that expression of CD169+ macrophages was dramatically lower in spleen sections of Nrf2-/- mice than in Nrf2+/+ control mice. We hypothesized that our macrophage-deficient mice would display a defect in recovery from blood loss. Five to seven days after acute blood loss, immature erythroid progenitors (CD71hiTer119hi) increased in marrow by about 5-fold in Nrf2+/+ mice (p≤0.001, Fig. 1b), and mature erythroid progenitors (CD71loTer119hi) increased in marrow by 12-fold (p≤0.05) but the erythroid marrow response was impaired significantly in the macrophage deficient Nrf2-/- mice. To extend our observations regarding macrophage deficiency and impaired erythroid response, we chose a more functional outcome of recovery from anemia after high-grade blood loss produced by daily phlebotomies over 3 consecutive days to induce stress erythropoiesis in Nrf2+/+ and Nrf2-/- mice. We found significantly lower packed cell volume values specifically on Days 2, 4 and 10, implying delayed erythroid recovery (p≤0.05, two-way ANOVA). The Nrf2-/- mice also showed a significant decline in total hemoglobin than the Nrf2+/+ mice (p≤0.05). Additionally, peripheral blood reticulocyte response to blood loss is delayed in Nrf2 deficient mice compared to age-matched controls (11.0 ± 0.6% vs. 14.8 ± 0.6%, p≤0.001). We analyzed expression of heme-oxygenase 1 (HO-1), a well-known Nrf2-regulated gene. HO-1 mRNA expression increased 3-fold and 23-fold in Nrf2+/+ mice animals subjected to phlebotomy and hemin treatment compared to 2-fold and 12-fold expression in Nrf2-deficient mice (p≤0.05). We demonstrate for the first time that Nrf2-deficient mice have a deficiency of macrophages that includes subsets considered erythroblastic island (EI) macrophages, and that this deficiency is associated with impaired erythroid response to induced stress. Secondly, our multiple phlebotomies data in aggregate demonstrate that Nrf2-/- mice deficient in BM macrophages have significant delay in functional erythroid response and recovery from experimentally-induced anemia. Thirdly, impaired inducibility of HO-1 is a known feature of Nrf2-/- mice, which we confirmed in our results, could be contributing to the impairment in erythroid response. However, it is not likely that restricted iron trafficking to erythroid progenitors occurs in Nrf2-/- mice, since there is no characteristic alteration of mean corpuscular volume and mean corpuscular hemoglobin in peripheral blood. This is an area worthy of additional investigation. We conclude that the Nrf2 gene plays a previously unappreciated role in erythroid biology that appears to be mediated through macrophage function. Disclosures Ofori-Acquah: Shire Human Genetic Therapies Inc: Other: Financial Relationship. Kato:Bayer: Research Funding; Novartis, Global Blood Therapeutics: Consultancy, Research Funding.

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.

scholarly journals Inflammation induces stress erythropoiesis through heme-dependent activation of SPI-C

2019 ◽  
Vol 12 (598) ◽  
pp. eaap7336 ◽  
Author(s):  
Laura F. Bennett ◽  
Chang Liao ◽  
Michael D. Quickel ◽  
Beng San Yeoh ◽  
Matam Vijay-Kumar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Proinflammatory Cytokines ◽  
Lymphoid Cells ◽  
Sterile Inflammation ◽  
Erythroid Progenitors ◽  
Gene Encoding ◽  
Immune Effector ◽  
Effector Cells ◽  
Stress Erythropoiesis

Inflammation alters bone marrow hematopoiesis to favor the production of innate immune effector cells at the expense of lymphoid cells and erythrocytes. Furthermore, proinflammatory cytokines inhibit steady-state erythropoiesis, which leads to the development of anemia in diseases with chronic inflammation. Acute anemia or hypoxic stress induces stress erythropoiesis, which generates a wave of new erythrocytes to maintain erythroid homeostasis until steady-state erythropoiesis can resume. Although hypoxia-dependent signaling is a key component of stress erythropoiesis, we found that inflammation also induced stress erythropoiesis in the absence of hypoxia. Using a mouse model of sterile inflammation, we demonstrated that signaling through Toll-like receptors (TLRs) paradoxically increased the phagocytosis of erythrocytes (erythrophagocytosis) by macrophages in the spleen, which enabled expression of the heme-responsive gene encoding the transcription factor SPI-C. Increased amounts of SPI-C coupled with TLR signaling promoted the expression ofGdf15andBmp4, both of which encode ligands that initiate the expansion of stress erythroid progenitors (SEPs) in the spleen. Furthermore, despite their inhibition of steady-state erythropoiesis in the bone marrow, the proinflammatory cytokines TNF-α and IL-1β promoted the expansion and differentiation of SEPs in the spleen. These data suggest that inflammatory signals induce stress erythropoiesis to maintain erythroid homeostasis when inflammation inhibits steady-state erythropoiesis.

scholarly journals A Shared Signaling Network That Maintains Erythroid Homeostasis By Activating Stress Erythropoiesis Regulates Inflammation: Implications for the Anemia of Chronic Inflammation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 629-629
Author(s):  
James Fraser ◽  
Adwitia Dey ◽  
Shaneice Nettleford ◽  
Siyang Hao ◽  
Luming Zhao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Steady State ◽  
Inflammatory Cytokines ◽  
Red Cell ◽  
Erythroid Progenitors ◽  
Stress Erythropoiesis ◽  
Inflammatory Signals ◽  
Treg Development ◽  
Pro Inflammatory Cytokines

Abstract Anemia is a common secondary pathology resulting from inflammatory diseases including cancer or infection. Its exact prevalence is difficult to determine, yet its contributions to the morbidity and mortality of patients and its negative impact on quality of life are clear. Despite the diverse set of factors that can lead to inflammatory anemia, its core pathology of hyperinflammation, iron dysregulation, and lack of red cell production suggests the possibility of a common etiology. Inflammation induces pro-inflammatory cytokines including TNFα, IL-1β and IFNγ that drive myelopoiesis at the expense of steady state bone marrow erythropoiesis. In addition, other cytokines increase the expression of hepcidin, haptoglobin and hemopexin by the liver, leading to the sequestration of iron. While limiting iron can be beneficial in the context of infection, the consequence of this restriction is a further reduction in red cell production in the bone marrow. To compensate for the loss of bone marrow erythropoiesis, inflammation induces stress erythropoiesis in the spleen or liver. Stress erythropoiesis is regulated by different signals which include BMP4 and GDF15 and utilizes stress erythroid progenitors that are distinct from steady state erythroid progenitors. Our work shows that in contrast to steady state erythropoiesis, pro-inflammatory cytokines like TNFα promote the proliferation of stress erythroid progenitors, while anti-inflammatory signals such as PGJ2 and IL-10 promote their differentiation. These studies demonstrate that the expansion and differentiation stages of stress erythropoiesis are coordinated with, and influenced by, signals that initiate and resolve inflammation. In addition, we show that this regulation is reciprocal. Signals that regulate the differentiation of stress erythroid progenitors (GDF15 and BMP4) promote the resolution of inflammation. Mice infected with the model gut pathogen Citrobacter rodentium, exhibit stress erythropoiesis in the spleen, while steady state erythropoiesis in the bone marrow is suppressed until pathogen clearance. We observed that hepcidin expression in the liver increases initially, but then decreases as the expression of erythroferrone by stress erythroid progenitors increased in the spleen, but not the bone marrow. Using mice mutant for GDF15 (GDF15-/-) and for BMP4 signaling (flexed-tail f/f), which exhibit defective stress erythropoiesis, we observed that the expression of hepcidin was dysregulated suggesting that stress erythroid progenitors are responsible for iron regulation at this time. In addition, infection of mutant mice led to increased lethality. During peak infection, we observed morphological differences in the colons of these mice indicative of increased inflammation and systemic infection. These changes were associated with increased expression of pro-inflammatory genes, as well as decreased numbers of FoxP3+ regulatory T-cells (Tregs). Using naïve CD4+ T-cells isolated from uninfected control, f/f or GDF15-/- mice, we observed significantly altered gene expression from mutant T-cells following Treg induction in vitro. However, the addition of BMP4 and GDF15 into these cultures rescued Treg development of mutant naïve T-cells and enhanced Treg development of naïve control T cells. Analysis of the BMP4 and GDF15 signaling pathways in both stress erythroid progenitor differentiation and in Treg development revealed that in both systems these signals converge on the transcription factor HIF1α. Taken together these data support a new model showing that the loss of steady state erythropoiesis due to pro-inflammatory signals is balanced by the activation of stress erythropoiesis by those same factors. Similarly, the differentiation of stress erythroid progenitors appears to regulate iron, and is itself regulated by the same signals that drive the development of Tregs and the expression of anti-inflammatory cytokines during immune resolution. This work supports a novel model where initiation and resolution of inflammatory immune responses are co-regulated with stress erythropoiesis, which allows for a robust immune response while maintaining erythroid homeostasis. Furthermore, this model predicts that alterations to this shared signaling network will underlie the development of chronic inflammatory anemia. Disclosures No relevant conflicts of interest to declare.

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