Transferrin receptor 1 is required for enucleation of mouse erythroblasts during terminal differentiation

Aoto, Mamoru; Iwashita, Akiho; Mita, Kanako; Ohkubo, Naoaki; Tsujimoto, Yoshihide; Mitsuda, Noriaki

doi:10.1002/2211-5463.12573

Cited by 10 publications

(7 citation statements)

References 31 publications

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“…Post burn M-CSF blockade led to a further impairment of medullary erythropoiesis that was most apparent at or near the orthochromatic erythroblast stage. The further reduction of erythroid cellularity caused by post burn M-CSF blockade may have occurred due to augmented G-CSF secretion since we previously found G-CSF impairs medullary erythropoiesis in ACI mice 10 or because iron restriction impairs late stage differentiation and enucleation 48,49 . The augmented G-CSF secretion likely contributed to the systemic neutrophil increase we measured in burn injured mice subjected to M-CSF blockade because we previously determined the post burn neutrophil increase is G-CSF dependent 11 .…”

Section: Discussionmentioning

confidence: 99%

M-CSF supports medullary erythropoiesis and erythroid iron demand following burn injury through its activity on homeostatic iron recycling

Noel

Ramser

Pitstick

et al. 2022

Sci Rep

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M-CSF receptor signaling supports the development and survival of mononuclear phagocytes and is thought to play a role in post burn anemia by promoting myeloid lineage bias. We found M-CSF secretion was increased in burn patients and a murine model of post burn ACI, so we neutralized M-CSF in ACI mice to determine if erythropoiesis was improved. Instead, M-CSF blockade further impaired erythropoiesis and erythroid cells access to iron. M-CSF blockade enhanced inflammatory cytokine secretion, further increased systemic neutrophil counts, and led to tissue iron sequestration that was dependent, in part, on augmented IL-6 secretion which induced hepcidin. Deleterious effects of post burn M-CSF blockade were associated with arrest of an iron recycling gene expression signature in the liver and spleen that included Spi-C transcription factor and heme oxygenase-1, which promote heme metabolism and confer a non-inflammatory tone in macrophages. Hepatic induction of these factors in ACI mice was consistent with a recovery of ferroportin gene expression and reflected an M-CSF dependent expansion and differentiation of Spi-C+ monocytes into Kupffer cells. Together, this data indicates M-CSF secretion supports a homeostatic iron recycling program that plays a key role in the maintenance of erythroid cells access to iron following burn injury.

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Section: Discussionmentioning

confidence: 99%

M-CSF supports medullary erythropoiesis and erythroid iron demand following burn injury through its activity on homeostatic iron recycling

Noel

Ramser

Pitstick

et al. 2022

Sci Rep

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“… 61 Other iron supplements that could be tested include reagents that would deliver iron to erythroid cells in a CD71-independent manner. These include the small lipophilic molecule hinokitiol that can carry iron across the cell membrane into erythroid cells 62 , 63 or alternatively, ferric carboxymaltose and iron sucrose, both already prescribed to patients suffering from iron deficiency. 64 …”

Section: Holotransferrinmentioning

confidence: 99%

Towards manufactured red blood cells for the treatment of inherited anemia

2021

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Patients with inherited anemia and hemoglobinopathies (such as sickle cell disease and β-thalassemia) are treated with red blood cell (RBC) transfusions to alleviate their symptoms. Some of these patients may have rare blood group types or go on to develop alloimmune reactions, which can make it difficult to source compatible blood in the donor population. Laboratory-grown RBC represent a particularly attractive alternative which could satisfy an unmet clinical need. The challenge, however, is to produce - from a limited number of stem cells - the 2x1012 RBC required for a standard adult therapeutic dose. Encouraging progress has been made in RBC production from adult stem cells under good manufacturing practice. In 2011, the Douay group conducted a successful proof-of-principle mini-transfusion of autologous manufactured RBC in a single volunteer. In the UK, a trial is planned to assess whether manufactured RBC are equivalent to RBC produced naturally in donors, by testing an allogeneic mini-dose of laboratory-grown manufactured RBC in multiple volunteers. This review discusses recent progress in the erythroid culture field as well as opportunities for further scaling up of manufactured RBC production for transfusion practice.

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“…18 Specifically, clathrin-mediated vesicle trafficking is required for enucleation. 18,41 To gain further insights into the mechanisms by which the ERK pathway inhibits enucleation, we investigated whether U0126 affects clathrin-dependent endocytosis by monitoring internalization of CD71 (transferrin receptor) that mediates the uptake of transferrin via clathrin-dependent endocytosis. 42 We used flow cytometry to examine the surface expression of CD71.…”

Section: Inhibition Of Erk1/2 Activation Inhibits Clathrinmediated Endocytosis In Human Orthochromatic Erythroblastsmentioning

confidence: 99%

Vesicular formation regulated by ERK/MAPK pathway mediates human erythroblast enucleation

Huang

et al. 2021

Blood Advances

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Enucleation is a key event in mammalian erythropoiesis responsible for generation of enucleated reticulocytes. While progress is being made in developing mechanistic understanding of enucleation, our understanding of mechanisms for enucleation is still incomplete. Mitogen-activated protein kinase (MAPK) pathway plays diverse roles in biological processes but its role in erythropoiesis is yet to be fully defined. Analysis of RNA-seq data revealed that MAPK pathway is significantly up regulated during human terminal erythroid differentiation. MAPK pathway consists of three major signaling cassettes, MEK/ERK, p38 and c-Jun N-terminal Kinases (JNK). In the present study, we show that amongst these three cassettes, only ERK was significantly up regulated in late stage human erythroblasts. The increased expression of ERK along with its increased phosphorylation suggests a potential role of ERK activation in enucleation. To explore this hypothesis, we treated sorted populations of human orthochromatic erythroblasts with MEK/ERK inhibitor U0126 and found that U0126 inhibited enucleation. In contrast, inhibitors of either p38 or JNK had no effect on enucleation. Mechanistically, U0126 selectively inhibited formation/accumulation of cytoplasmic vesicles and endocytosis of the transferrin receptor without affecting chromatin condensation, nuclear polarization and enucleosome formation. Treatment with vacuolin-1 that induces vacuole formation partially rescued the blockage of enucleation by U0126. Moreover, phosphoproteomic analysis revealed that inactivation of the ERK pathway led to down regulation of endocytic recycling pathway. Collectively, our findings uncovered a novel role of ERK activation in human erythroblast enucleation by modulating vesicle formation and have implications for understanding anemia associated with defective enucleation.

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Transferrin receptor 1 is required for enucleation of mouse erythroblasts during terminal differentiation

Cited by 10 publications

References 31 publications

M-CSF supports medullary erythropoiesis and erythroid iron demand following burn injury through its activity on homeostatic iron recycling

M-CSF supports medullary erythropoiesis and erythroid iron demand following burn injury through its activity on homeostatic iron recycling

Towards manufactured red blood cells for the treatment of inherited anemia

Vesicular formation regulated by ERK/MAPK pathway mediates human erythroblast enucleation

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