Cardiac-immune microniches programme macrophage states in the regenerating heart

Ehsan Razaghi, Selin Tüzüner, Trishalee Gungoosingh, Kerem Çil, Wan Shern Wong, Rita Alonaizan, Rebecca Richardson, Filipa C. Simões

Posted on: 19 May 2026

Preprint posted on 7 March 2026

Aquatic adventures in heart regeneration; The authors study zebrafish hearts after cryoinjury to identify ligand-receptor circuits and macrophage states that facilitate regeneration.

Selected by Theodora Stougiannou

Categories: cell biology, developmental biology

Aquatic adventures in heart regeneration; The authors study zebrafish hearts after cryoinjury to identify ligand-receptor circuits and macrophage states that facilitate regeneration.

Myocardial infarction & Immune reactions in tissue repair

Local tissue responses after myocardial injury differ between vertebrates that normally do not regenerate their tissues and vertebrates that do. In the former, local tissue injury is associated with various forms of cell death, which is then followed by activation of immune cell populations, clearance of cellular debris and generally, replacement with a connective tissue scar driven by fibroblast activation and extracellular matrix (ECM) deposition (Razaghi et al., 2026) [1].On the contrary, vertebrate species exhibiting regenerative capabilities – including zebrafish and axolotl – exhibit an immune response that aims to repair the acute myocardial injury and allows for the restoration of local tissue. This immune response is dependent upon macrophages, both resident as well as recruited populations [1].

The function of these macrophage populations depends on their environment; for example, scar-prone environments compel activation of fibrotic programmes and pro-regenerative niches compel activation of reparative programmes (Razaghi et al., 2026) [1]. These specialized locations have been described as niches; multiple such areas have been identified in the human heart.

Regenerative niches are a specialized type of cardiac niche that have been poorly defined so far. Specifically, spatial resolution of these niches is still lacking. At this point, more information is required on the organization of the cellular populations in the micro-niches present in the heart. Namely, information is needed relevant to the immune populations present and their relation to adjacent cardiac structural cells, the cellular crosstalk occurring between cell populations and finally, the local environment characteristics that compel activation of the various macrophage cell states. It is these macrophage states that could affect the balance between fibrosis and tissue regeneration [1].

What are the authors looking at?

The authors of the preprint used both single-cell and spatial transcriptomics, along with niche-aware computational modeling methods, to obtain knowledge relevant to local cellular organization, as well as cellular crosstalk between different cell populations in the micro-niche. This also allows for the identification of the local environmental processes that compel macrophage state, according to epicardial, fibrosis and vascular programmes. They eventually identified ligand-receptor circuits and macrophage states that facilitate regeneration. To this end, the authors isolated samples from homeostatic, sham-operated and cryoinjury zebrafish ventricles.

Key aspects of the study

Discrete macrophage populations, characterized by mpeg1.1 expression (mpeg1.1+ macrophages) could be identified during both homeostatic and regenerative states. These macrophage populations predominated, and at the same time co-existed with, other innate and adaptive immune populations. This has been identified 5 days post injury (dpi), a time when both pro-inflammatory and anti-inflammatory signatures exist in the injured myocardium [1].
During cryoinjury, mpeg1.1+ macrophage populations expanded even further, whilst mpeg1.1+ NK-cells declined across all conditions. DC and B-lymphocyte remained stable in most groups.
Functions across a mpeg1.1+ macrophage population were identified based on gene-module analysis, thus assigning different macrophages their likely roles in the injured heart – detailed in the table below (Table 1).

Table 1 Summary of macrophage expression profiles identified in the study [1].

Macrophages, under conditions of homeostasis, were found in sparse epicardial and perivascular regions; in the heart of vertebrate species exhibiting regenerative capabilities, these macrophages would localize around areas of injury and in the epicardial layer during conditions of regeneration (as observed by spatial mapping, ligand-receptor-target inference experiments) [1].
Interactions between these macrophage subsets and the underlying structural landscape occurred in several, discrete micro-environments, or niches, in the regenerating heart; each niche exhibited a specific cellular population, with discrete signaling circuits. Examples of such micro-niches include the epicardial layer and the subepicardial fibroblasts; both carry out directives associated with the outer area of the lesion [1].
Local fibroblasts secreted interleukin-34 (Il34), which binds to Csf1ra, a receptor found on macrophages;macrophages present in the area of injury – particularly macrophages with a resident and pro-resolving-clearance profile – in turn upregulated egr1. This created a local micro-environment that favours regeneration, dampens and restrains excessive fibrosis, supports vascular integrity and epicardial signalling programmes [1].
Conversely, hearts that cannot regenerate, cannot signal effectively and shift macrophage states towards phagolysosomal and stress-adapted inflammatory profiles, with an associated expansion in fibroblast micro-niches and compromised endothelial and epicardial phenotypes. Overall, this creates a pro-fibrotic repair response [1].

Why this work is interesting

Most clinical cardiovascular research today focuses on the identification of injury pathways, so that they may be prevented or targeted, after the injury occurs. But what if we could attempt actual regeneration? Studies in vertebrate species that exhibit regeneration, such as the zebrafish, allows for the elucidation of these regeneration pathways. Perhaps if humans can find out exactly what regenerating species are “doing right”, they might learn to do it as well.

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Questions to the authors

On macrophage states: In your research, you identify several macrophage profiles, which in turn are characterized by different gene expression signatures. Do these represent different populations, or can one macrophage dynamically change from one state to the other?
- Are resident macrophages more prone to adopting specific profiles versus macrophages recruited from circulating monocytes?

Regarding macrophage states, our view is that these are best understood as functional states rather than fixed, permanently distinct populations. The single cell and spatial data show macrophages occupying transcriptional programmes associated with inflammation, antigen presentation, phagocytosis, resolution, remodelling, metabolism etc. Some of these states are likely enriched in cells of different origins but the data also support a high degree of plasticity, with macrophages dynamically responding to the local tissue environment. This is particularly important in the regenerating heart, where spatially restricted signals from fibroblasts, epicardial cells and other structural cells appear to programme macrophage behaviour within defined microniches.

On resident versus recruited macrophages, our data suggest that resident-like macrophages are particularly associated with specific pro-regenerative programmes. For example, csf1ra-expressing resident and pro-resolving macrophage states respond to fibroblast-derived il34 and activate an egr1-associated programme. This axis appears to be important for restraining excessive fibrosis and supporting vascular and epicardial signalling. By contrast, when csf1ra signalling is disrupted, macrophages shift towards stress-adapted inflammatory states and the tissue environment becomes more pro-fibrotic. We therefore think that macrophage origin matters but that local microniche signals are a major determinant of macrophage state and function.

On micro-niches & future applications: In your article, it becomes clear that cells will adopt different states, depending on the microenvironment they are found in. Do you think this opens a pathway for creating “injectable micro-niches” as a cell therapy module aimed at tissue regeneration?

Regarding “injectable microniches” this is an exciting long-term possibility, although we would be cautious about translating the concept too directly at this stage. Our work suggests that effective regeneration is unlikely to be achieved by delivering a single cell type or factor in isolation.

Instead, regenerative outcomes may require recreating specific combinations of cellular interactions, ligand-receptor signals and spatial organisation. In that sense, the idea of engineering a pro-regenerative microenvironment, whether through biomaterials, targeted delivery of niche factors or cell-derived based approaches, is very attractive indeed. The key challenge will be to deliver them in a way that is spatially and temporally controlled.

More broadly, we hope this work helps shift the focus from macrophages as broadly “good” or “bad” in post-injury repair, towards a more precise view in which macrophage function is programmed by local tissue context. Understanding these cardio-immune microniches may provide new entry points for re-engineering fibrotic repair towards regeneration.

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