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| Status |
Public on Jan 25, 2022 |
| Title |
Deviated myeloid differentiation in SCD mice under heme stress II. |
| 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 |
Single cell suspension positively enriched for macrophages using F4/80 magnetic beads from a spleen of a SCD and wild-type mouse subjected to droplet-based single-RNA sequencing (10x genomics).
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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 (2) |
| GSM5416217 |
single cell suspension positively enriched for macrophages using F4/80 magnetic beads from a spleen of a wild-type mouse |
| GSM5416218 |
single cell suspension positively enriched for macrophages using F4/80 magnetic beads from a spleen of a SCD mouse |
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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 |
PRJNA743345 |
| SRA |
SRP326708 |
