Preprint
Cardiac-immune microniches programme macrophage states in the regenerating heart
- Abstract:
- Adult zebrafish regenerate their hearts after injury, a process that requires macrophages, yet how local tissue microenvironments instruct macrophage states and function remains unclear. Here we combine single cell RNA sequencing with Visium and high-resolution MERFISH spatial transcriptomics to map the cardio-immune landscape of homeostatic and regenerating zebrafish hearts. We identify a mpeg1.1+ compartment comprising macrophages, dendritic, B and NK-like cells, and show that injury establishes a macrophage-centred immune environment with transcriptional programmes spanning resident surveillance, damage sensing, inflammation, antigen presentation, resolution and metabolic support. Communication-aware spatial modelling reveals that these states are not randomly distributed but organised into discrete structural-immune microniches across the injury region, each defined by stereotyped cellular compositions and ligand-receptor circuits. Within a fibroblast-macrophage microniche, we uncover an il34-csf1ra-egr1 axis in which col12a1a+ il34+ fibroblasts promote an egr1 pro-regenerative macrophage state that couples fibrosis, vascular integrity and epicardial signalling. We show that disruption of this axis by csf1ra loss of function reduces macrophage-, endothelial- and epicardial-rich microniches, amplifying fibroblast-driven domains that shift macrophages towards stress and long-sustained inflammatory programmes, thereby biasing early injury response towards a pro-fibrotic state. Our work establishes spatially defined cardio-immune microniches as key organisers of macrophage function and regenerative outcome, providing a mechanistic framework and actionable targets for reprogramming cardiac repair.
- Publication status:
- Published
- Peer review status:
- Not peer reviewed
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- Files:
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(Preview, Pre-print, pdf, 39.9MB, Terms of use)
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- Preprint server copy:
- 10.64898/2026.03.05.709830
Authors
+ British Heart Foundation
More from this funder
- Funder identifier:
- https://ror.org/02wdwnk04
- Grant:
- FS/IBSRF/21/25088
- RE/18/3/34214
- Preprint server:
- bioRxiv
- Publication date:
- 2026-03-07
- DOI:
- Language:
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English
- Pubs id:
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2395937
- Local pid:
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pubs:2395937
- Deposit date:
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2026-05-13
- ARK identifier:
Terms of use
- Copyright holder:
- Razaghi et al.
- Copyright date:
- 2026
- Rights statement:
- The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license.
- Licence:
- CC Attribution (CC BY)
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