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

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

Blood ◽

10.1182/blood.v106.11.4195.4195 ◽

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.

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

Blood ◽

10.1182/blood-2007-09-115121 ◽

2008 ◽

Vol 111 (8) ◽

pp. 4375-4385 ◽

Cited By ~ 57

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.

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

Blood ◽

10.1182/blood.v106.11.1351.1351 ◽

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.

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Complete Spatial Mapping of Steady-State and Stress Erythropoiesis

Blood ◽

10.1182/blood-2020-142973 ◽

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.

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

Blood ◽

10.1182/blood-2009-09-242487 ◽

2010 ◽

Vol 115 (18) ◽

pp. 3686-3694 ◽

Cited By ~ 31

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.

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

Science Signaling ◽

10.1126/scisignal.aap7336 ◽

2019 ◽

Vol 12 (598) ◽

pp. eaap7336 ◽

Cited By ~ 12

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.

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Podocalyxin Is a Selective Marker of Erythroid Progenitors but Is Dispensable for Anemia Recovery.

Blood ◽

10.1182/blood.v110.11.1731.1731 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1731-1731

Author(s):

Michael R. Hughes ◽

Steven Maltby ◽

Lori Zbytnuik ◽

Robert Paulson ◽

Kelly M. McNagny

Keyword(s):

Bone Marrow ◽

Peripheral Blood ◽

Health Research ◽

Red Cell ◽

Chimeric Mice ◽

Erythroid Progenitors ◽

Normal Peripheral Blood ◽

Stress Erythropoiesis ◽

Chemically Induced ◽

Erythroid Development

Abstract Podocalyxin, a member of the CD34-family of anti-adhesins, is induced on erythroid cells in the spleen and bone marrow following administration of high concentrations of erythropoietin (Epo), or, phenylhydrazine (PHz)-induced anemia. Notably, Podocalyxin is not expressed on committed erythroid progenitors during homeostatic red cell turnover. Our previous work has suggested that stress erythropoiesis in the mouse draws on a specific population of resident splenic erythroid progenitors which respond to a distinct set of signals during anemic recovery in contrast to the erythroid populations residing primarily in the marrow responsible for maintaining normal homeostasis (Lenox et al., 2005, Blood; Perry et al., 2007, Blood). During stress erythropoiesis, Podocalyxin expression is upregulated, in part, via a Stat5-dependent pathway in response to Epo (Sathyanarayana et al., 2007, Blood) and Podocalyxin expression has been postulated to play a key role in the release of reticulocytes into the periphery. In this work, we have addressed this hypothesis and further characterized the expression pattern of Podocalyxin during stress erythropoiesis. Since Podocalyxin (Podxl) gene deletion results in perinatal lethality (Doyonnas et al., 2001, J. Exp. Med), we used hematopoietic cell-reconstituted chimeric mice lacking Podocalyxin expression in their hematopoietic compartment. Ten weeks after transplantation, chimeric mice were demonstrated to have normal peripheral blood red cell and platelet homeostasis. Chimeric mice were subjected to Epo stimulation or chemically-induced models of anemia. We found that during stress erythropoiesis, Podocalyxin is rapidly upregulated on early erythroid precursors, with expression on populations with BFU-e and CFU-e, although not CFU-GM, potential. Podocalyxin expression continues through a proerythroblast stage of erythroid development and is maintained on immature reticulocytes in the periphery. While Podocalyxin is highly expressed on erythroblasts and progenitors during anemic stress recovery, we found that loss of Podocalyxin has no major influence on the proportion of erythroid progenitors and staged erythroblasts in the spleen and marrow in response to Epo and, further, Podocalyxin is dispensable for efficient recovery from chemically-induced models of anemia. Our findings suggest that Podocalyxin expression is not critical for reticulocyte release or efficient stress erythroid differentiation. We speculate that Podocalyxin may play a subtle role in early erythroid development during anemic recovery, population of bone marrow and spleen during late embryonic development or establishment of neo-natal homeostasis. Furthermore, we suggest Podocalyxin may be used as a highly specific marker to sort stress-induced BFU-e and CFU-e progenitors from lineage-marker depleted bone marrow, spleen or peripheral blood. MRH and SM contributed equally to this work and are fellows of the Strategic Training Program in Transfusion Science funded by the Canadian Institutes for Health Research (CIHR) and the Heart and Stroke Foundation of Canada at the University of British Columbia Centre for Blood Research(CBR). RFP holds a research grant from the National Blood Foundation(USA). KMM is a Michael Smith Foundation for Health Research Scholar and CBR Member.

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The critical role of T cells in glucocorticoid-induced osteoporosis

Cell Death and Disease ◽

10.1038/s41419-020-03249-4 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Lin Song ◽

Lijuan Cao ◽

Rui Liu ◽

Hui Ma ◽

Yanan Li ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Steady State ◽

Side Effects ◽

Critical Role ◽

Wild Type ◽

Receptor Activator ◽

Steady State Levels ◽

Induced Apoptosis

AbstractGlucocorticoids (GC) are widely used clinically, despite the presence of significant side effects, including glucocorticoid-induced osteoporosis (GIOP). While GC are believed to act directly on osteoblasts and osteoclasts to promote osteoporosis, the detailed underlying molecular mechanism of GC-induced osteoporosis is still not fully elucidated. Here, we show that lymphocytes play a pivotal role in regulating GC-induced osteoporosis. We show that GIOP could not be induced in SCID mice that lack T cells, but it could be re-established by adoptive transfer of splenic T cells from wild-type mice. As expected, T cells in the periphery are greatly reduced by GC; instead, they accumulate in the bone marrow where they are protected from GC-induced apoptosis. These bone marrow T cells in GC-treated mice express high steady-state levels of NF-κB receptor activator ligand (RANKL), which promotes the formation and maturation of osteoclasts and induces osteoporosis. Taken together, these findings reveal a critical role for T cells in GIOP.

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Dynamic changes in murine erythropoiesis from birth to adulthood: implications for the study of murine models of anemia

Blood Advances ◽

10.1182/bloodadvances.2020003632 ◽

2020 ◽

Vol 5 (1) ◽

pp. 16-25

Author(s):

Lixiang Chen ◽

Jie Wang ◽

Jing Liu ◽

Hua Wang ◽

Christopher D. Hillyer ◽

...

Keyword(s):

Bone Marrow ◽

Steady State ◽

Hemoglobin Concentration ◽

Red Cell ◽

Murine Models ◽

Erythropoietic Activity ◽

Dynamic Changes ◽

Newborn Mice ◽

Mean Cell Volume ◽

Cell Parameters

Abstract Liver, spleen, and bone marrow are 3 key erythropoietic tissues in mammals. In the mouse, the liver is the predominant site of erythropoiesis during fetal development, the spleen responds to stress erythropoiesis, and the bone marrow is involved in maintaining homeostatic erythropoiesis in adults. However, the dynamic changes and respective contributions of the erythropoietic activity of these tissues from birth to adulthood are incompletely defined. Using C57BL/6 mice, we systematically examined the age-dependent changes in liver, spleen, and bone marrow erythropoiesis following birth. In addition to bone marrow, the liver and spleen of newborn mice sustain an active erythropoietic activity that is gradually lost during first few weeks of life. While the erythropoietic activity of the liver is lost 1 week after birth, that of the spleen is maintained for 7 weeks until the erythropoietic activity of the bone marrow is sufficient to sustain steady-state adult erythropoiesis. Measurement of the red cell parameters demonstrates that these postnatal dynamic changes are reflected by varying indices of circulating red cells. While the red cell numbers, hemoglobin concentration, and hematocrit progressively increase after birth and reach steady-state levels by week 7, reticulocyte counts decrease during this time period. Mean cell volume and mean cell hemoglobin progressively decrease and reach steady state by week 3. Our findings provide comprehensive insights into developmental changes of murine erythropoiesis postnatally and have significant implications for the appropriate interpretation of findings from the variety of murine models used in the study of normal and disordered erythropoiesis.

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