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| Status |
Public on Dec 18, 2019 |
| Title |
Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The adult mammalian heart heals after myocardial infarction (MI) by deposition of scar tissue, leading to downstream arrhythmia, remodelling and heart failure1. In contrast, adult zebrafish and neonatal mouse hearts are capable of regenerating after injury. Macrophages are key mediators of tissue repair and appear to be required for both regeneration and healing by scar formation, but the mechanisms underlying these distinct roles are poorly understood2-4. Here we investigated how macrophages differentially influence the mode of repair by determining their responses in scar-free versus scar-induced healing, comparing ventricular resection with cryo-injured adult zebrafish hearts and neonatal versus adult mouse hearts after MI. Unbiased transcriptomics revealed molecular programmes implicating macrophages in the initiation and resolution of inflammation to dictate the kinetics of scarring during zebrafish regeneration and the activation of direct and indirect pathways to drive fibrosis in the adult mouse heart. Most notably we observed up-regulation of collagen isoforms in both zebrafish and mouse macrophages following injury. Adoptive transfer of macrophages, from resected zebrafish hearts into cryo-injured hosts and splenic monocyte-derived macrophages from adult mouse donors into neonatal hearts, enhanced scar formation and induced fibrosis, respectively, via cell autonomous production of collagen. In zebrafish, macrophage-specific targeting of collagen 4a binding protein and cognate collagen 4a1 followed by transfer led to significantly reduced scarring in cryo-injured hosts, as further evidence of a direct macrophage contribution to collagen deposition and scar formation. These findings contrast with the current model of scarring, whereby collagen is laid down exclusively by myofibroblasts, and implicate macrophages as critical regulators of heart repair.
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| Overall design |
RNA sequencing of cardiac macrophages following myocardial infarction in the neonatal and adult mouse
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| Contributor(s) |
Cahill TJ, Simões FC, Kenyon A, Gavriouchkina D, Lemieux ME, Barnette DN, Rohling M, Weinberger M, Masmanian E, Williams R, Greaves DR, Choudhury RP, Sauka-Spengler T, Riley PR |
| Citation(s) |
32001677 |
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| Submission date |
Feb 19, 2019 |
| Last update date |
Feb 10, 2020 |
| Contact name |
Thomas J Cahill |
| Organization name |
University of Oxford
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| Department |
Department of Physiology, Anatomy, & Genetics
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| Lab |
Riley
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| Street address |
Sherrington Building, Sherrington Rd
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| City |
Oxford |
| ZIP/Postal code |
OX1 3PT |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (28)
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| Relations |
| BioProject |
PRJNA523576 |
| SRA |
SRP186478 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE126772_annotated_fpkm.xls.gz |
2.0 Mb |
(ftp)(http) |
XLS |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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