# Editorial: Cardiac fibroblasts: from development to disease

Silvia C Hernandez, Thomas Moore-Morris, Adrian Ruiz-Villalba

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Silvia C Hernandez, Thomas Moore-Morris, Adrian Ruiz-Villalba. Editorial: Cardiac fibroblasts: from development to disease. Frontiers in Cell and Developmental Biology, 2025, 13, pp.1736508. 10.3389/fcell.2025.1736508. hal-05443438

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OPEN ACCESS

EDITED AND REVIEWED BY
Ramani Ramchandran,
Medical College of Wisconsin, United States

*CORRESPONDENCE

Thomas Moore-Morris,
✉ thomas.moore-morris@inserm.fr
Adrian Ruiz-Villalba,
✉ adruiz@uma.es

†These authors have contributed equally to this work

RECEIVED 31 October 2025

REVISED 22 November 2025

ACCEPTED 25 November 2025

PUBLISHED 02 December 2025

CITATION

Hernandez SC, Moore-Morris T and Ruiz-Villalba A (2025) Editorial: Cardiac fibroblasts: from development to disease. *Front. Cell Dev. Biol.* 13:1736508. doi: 10.3389/fcell.2025.1736508

COPYRIGHT

© 2025 Hernandez, Moore-Morris and Ruiz-Villalba. This is an open-access article distributed under the terms of the [Creative Commons Attribution License (CC BY)](https://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Editorial: Cardiac fibroblasts: from development to disease

Silvia C. Hernandez¹,², Thomas Moore-Morris³*† and Adrian Ruiz-Villalba⁴,⁵*†

¹The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States, ²Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States, ³IGF, Univ Montpellier, CNRS, Inserm, Montpellier, France, ⁴Department of Animal Biology, Faculty of Sciences, University of Málaga, Campus de Teatinos s/n, Málaga, Spain, ⁵Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (IBIMA Plataforma BIONAND), Málaga, Spain

KEYWORDS

cardiac fibroblasts, extracellular matrix, fibrosis, neutrophils, development, cardiac disease

## Editorial on the Research Topic

### Cardiac fibroblasts: from development to disease

Cardiac fibroblasts (CFs) have been a major focus of study in recent years in the field of cardiovascular research. They are the main cell-type responsible for producing and remodelling the extracellular matrix (ECM), a dynamic scaffold that supports cardiac cells during development, in health and upon cardiac injury (Cadosch et al., 2024). Thanks to the recent advances in high-throughput technologies, CFs are now recognized as a heterogeneous group of cells with diverse transcriptomic, developmental, and functional characteristics. However, our understanding of their functional heterogeneity, developmental origins, and interactions with other key components—such inflammatory cells and the extracellular matrix—remains incomplete in all these contexts. This Research Topic, *Cardiac Fibroblasts: From Development to Disease*, presents four novel contributions that address some of these open questions related to CF biology.

In their article, *Harrington and Moore-Morris*, provide a comprehensive review of current challenges associated with the specificity of CF markers in different contexts, resulting from the use of diverse genetic tools, antibodies for identification, and lineage tracing approaches in mice and zebrafish. These different approaches and models indicate that the embryonic epicardium is the main source of CFs during development, and that fibrosis primarily results from the activation of these cells, with minor contributions from other sources. In addition, the authors highlight the role of CFs in fibrosis across different heart failure models, such as myocardial infarction (MI) and transverse aortic constriction (TAC), and in regenerative models, such as zebrafish and neonatal mice, stressing the main differences between the two scenarios. Interestingly, the molecular pathways that regulate this fibrotic response are conserved across models: transforming growth factor-β (TGF-β), the renin-angiotensin-aldosterone system (RAAS), tumour necrosis factor-α (TNFα), Wingless/Int (Wnt), and more recently studied mediators such as endothelin-1, galectin-3, and interleukin 11, all play a role in the transition of homeostatic CFs into more responsive “activated CFs”, following injury.

Another universal feature of fibrosis is that it is exacerbated during old age. Hence, with the increasing pace of population ageing, understanding the mechanisms involved is highly significant, and it is essential to design cardiac remodeling studies aimed at developing
targeted therapies. For this reason, in their original article, Perreault
et al. decided to examine the effects of foetal and adult ECM
on fibroblast phenotypes. Their initial findings indicate that the
developmental age of the ECM influences CF activation and
migration rate and stiffness. Notably, CFs cultured on adult
compared to fetal ECM expressed higher levels of myofibroblast
marker αSMA. These differences were attenuated by stimulation
with TGF-β1, suggesting that ECM age-related effects on CF
biology were mediated by changes in TGF-β signalling. In line
with this, altered TGF-β signalling has been linked to ageing
(Ren et al., 2023), and the ECM plays a key role in determining
the distribution and activity of TGFβs and other signalling
molecules (Alshoubaki et al., 2023).

One of the most important factors in CF activation is
inflammation. Although many studies have focused on macrophage-
CF crosstalk (Frangogiannis, 2025), interactions of CFs with other
prominent immune cell types have been less explored. Recently,
neutrophils have been shown to contribute to fibrosis by modulating
fibroblast function, promoting healing and scar formation, and
depositing fibrotic matrix in wounds (Fischer et al., 2022). In
their original research, Anfossi et al. investigated CF-neutrophil
interaction, a relationship that is still poorly understood, using
primary rat CFs. Here, applying basic cellular and molecular
*in vitro* techniques, they demonstrated that CFs are more
responsive to interactions with neutrophils under inflammatory
conditions compared to basal conditions. Notably, this interaction
had a significant effect on the ECM due to the modulation
of Matrix Metalloproteinase (MMP) activity by neutrophils in
a paracrine manner. Interestingly, the authors concluded that
the effects of CF-neutrophil interactions are counteracted by
the interferon-beta (IFN-β)/Janus kinases (JAK) IFN-β/JAK
signalling pathway.

The molecular mechanisms downstream of the multiple
external cues that promote fibroblast activation, from quiescent
to pro-fibrotic “myofibroblast” state, are of high clinical interest.
Acharya et al. developed an innovative perspective on how RNA-
binding motif (RBM) proteins-dependent post-transcriptional
gene regulation contributes to this switch during pathological
cardiac remodeling. Their review highlights the importance of
alternative splicing regulation in CF biology mediated by different
classes of RBM proteins such as RNA binding Fox-1 homologs
(Rbfox), Muscleblind-like 1 (MBNL1), CUG-BP and ETR-3-like
factors (CELF), and serine/arginine-rich splicing factor (SRSF)
proteins. Among them, MBNL1 is suggested as a master regulator
of the transformation of CFs into their activated state. They also
highlighted the role of other RBM proteins in regulating the balance
between RNA stability and degradation and indicated that proteins
such as Human antigen R (HuR) also contribute to the transition of
CFs into a more fibrotic phenotype.

In summary, recent studies, including those featured in this
special issue, have enabled significant progress to be made on
defining CF origins, markers, heterogeneity, and interactions with
other cell types or ECM. However, shedding light on CF diversity
has brought new challenges to the field. These include reaching
a consensus on the characteristics that define CF populations
in developmental and pathological contexts. Furthermore, as for
other interstitial cell types present throughout the body, current
approaches for targeting CFs *in vivo* for functional studies, e.g.,

conditional deletion or AAV-mediated delivery, lack specificity and
efficiency. Addressing these hurdles will be critical for identifying
novel targets to regulate CF activity for clinical applications. We
extend our sincere gratitude to all the authors and reviewers for
their invaluable contributions. We hope this Research Topic will
inspire further collaborations and advance our understanding of
CF biology, ultimately accelerating the development of potential
therapeutic targets and personalized medicine.

Author contributions

SH: Writing – original draft, Project administration, Conceptualization, Investigation, Writing – review and editing. TM-M: Writing – review and editing, Conceptualization, Supervision, Investigation, Writing – original draft. AR-V: Conceptualization, Supervision, Funding acquisition, Investigation, Writing – review and editing, Writing – original draft.

Funding

The authors declare that financial support was received for
the research and/or publication of this article. This research was
supported by the Spanish Ministerio de Ciencia, Innovación y
Universidades (MICIU)/Agencia Estatal de Investigación (AEI)
[PID2020-119430RJ-I00; RYC21-034611-I; and CNS2022-135973
to AR.V.]; European Social Fund Plus [RYC21-034611-I to AR.V.];
and European Union NextGenerationEU/Plan de Recuperación,
Transformación y Resiliencia (PRTR) [CNS2022-135973 to AR.V.].

Conflict of interest

The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.

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References

Alshoubaki, Y. K., Lu, Y. Z., Legrand, J. M. D., Karami, R., Fossat, M., Salimova, E., et al. (2023). A superior extracellular matrix binding motif to enhance the regenerative activity and safety of therapeutic proteins. *NPJ Regen. Med.* 8 (1), 25. doi:10.1038/s41536-023-00297-0

Cadosch, N., Gil-Cruz, C., Perez-Shibayama, C., and Ludewig, B. (2024). Cardiac fibroblastic niches in homeostasis and inflammation. *Circ. Res.* 134 (12), 1703–1717. doi:10.1161/CIRCRESAHA.124.323892

Fischer, A., Wannemacher, J., Christ, S., Koopmans, T., Kadri, S., Zhao, J., et al. (2022). Neutrophils direct preexisting matrix to initiate repair in damaged tissues. *Nat. Immunol.* 23 (4), 518–531. doi:10.1038/s41590-022-01166-6

Frangogiannis, N. G. (2025). Targeting macrophage-fibroblast interactions in the failing heart. *Nat. Rev. Cardiol.* 22 (4), 223–224. doi:10.1038/s41569-024-01112-z

Ren, L. L., Miao, H., Wang, Y. N., Liu, F., Li, P., and Zhao, Y. Y. (2023). TGF-β as a master regulator of aging-associated tissue fibrosis. *Aging Dis.* 14 (5), 1633–1650. doi:10.14336/AD.2023.0222