|
| 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
|
| 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.
|
| |
|
| 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.
|
| |
|
| Contributor(s) |
Buzzi RM, Pfefferlé M, Schaer DJ, Vallelian F |
| Citation(s) |
35031770 |
| |
| Submission date |
Jul 02, 2021 |
| Last update date |
Jan 26, 2022 |
| Contact name |
Raphael Matthias Buzzi |
| E-mail(s) |
raphael.buzzi@usz.ch
|
| Organization name |
Universitätsspital and University of Zurich
|
| Department |
Division of Internal Medicine
|
| Street address |
Rämistrasse 100
|
| City |
Zürich |
| ZIP/Postal code |
8091 |
| Country |
Switzerland |
| |
|
| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
| Samples (1) |
| GSM5416214 |
Multiplexed BM-derived cell culture experiment |
|
| This SubSeries is part of SuperSeries: |
| GSE179365 |
Heme-activated Nrf2 signaling skews fate trajectories of bone marrow cells from dendritic cells towards macrophages |
|
| Relations |
| BioProject |
PRJNA743342 |
| SRA |
SRP326707 |
