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Status |
Public on Jan 25, 2022 |
Title |
Heme exposure shifts shifts myeloid differentiation in bone marrow derived mixed cell cultures. |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Heme is an erythrocyte-derived toxin that drives disease progression in hemolytic anemias. During hemolysis, specialized bone marrow-derived macrophages with a high heme-metabolism capacity orchestrate disease adaptation by removing damaged erythrocytes and heme-protein complexes from the blood and supporting iron recycling for erythropoiesis. Here, we performed single-cell RNA sequencing with RNA velocity analysis of GM-CSF-supplemented mouse bone marrow cultures to assess myeloid differentiation under heme stress. We found that heme-activated NRF2 signaling shifted the differentiation trajectories of cells towards antioxidant, iron-recycling macrophages at the expense of dendritic cells, as these cells were selectively deficient in heme-exposed bone marrow cultures. Heme eliminated the capacity of GM-CSF-supplemented bone marrow cultures to activate antigen-specific T cells. The generation of functionally competent dendritic cells was restored by NRF2 loss. The heme-induced phenotype was reproduced in hemolytic mice with sickle cell disease and spherocytosis and associated with reduced dendritic cell functions in the spleen. Our data provide a novel mechanistic underpinning how hemolytic stress may provoke hyposplenism-related secondary immunodeficiency, which is a critical determinant of mortality in patients with genetic hemolytic anemias.
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Overall design |
M-CSF- and GM-CSF-supplemented BM cell cultures were stimulated with heme (300μM) or albumin (control) on day 3. On day 7, the cells were harvested, tagged with DNA-barcoded antibodies, and pooled into a single scRNA-seq sample for sequencing.
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Contributor(s) |
Buzzi RM, Pfefferlé M, Schaer DJ, Vallelian F |
Citation(s) |
35031770 |
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Submission date |
Jul 02, 2021 |
Last update date |
Jan 26, 2022 |
Contact name |
Raphael Matthias Buzzi |
E-mail(s) |
raphael.buzzi@usz.ch
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Organization name |
Universitätsspital and University of Zurich
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Department |
Division of Internal Medicine
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Street address |
Rämistrasse 100
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City |
Zürich |
ZIP/Postal code |
8091 |
Country |
Switzerland |
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Platforms (1) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (1) |
GSM5416214 |
Multiplexed BM-derived cell culture experiment |
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This SubSeries is part of SuperSeries: |
GSE179365 |
Heme-activated Nrf2 signaling skews fate trajectories of bone marrow cells from dendritic cells towards macrophages |
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Relations |
BioProject |
PRJNA743342 |
SRA |
SRP326707 |