From fibrosis to regeneration: cardiac fibroblasts in adult acomys cahirinus

Abstract Cardiovascular diseases (CVD) remain the leading cause of death worldwide, with myocardial infarction (MI) as a main contributor (1, 2). Mortality stems from the growing prevalence of cardiovascular risk factors and poor regenerative capacity of the human heart (3, 4). Regenerative models such as zebrafish or neonatal rodents have provided valuable insights into cardiac regeneration, largely due to their ability to induce cardiomyocyte (CM) proliferation, something rarely achievable in the adult human heart (5). Recently, attention has turned to non-CM populations, particularly cardiac fibroblasts (CF), which play essential roles in tissue remodelling and extracellular matrix (ECM) production. Fibrosis, driven by CF activation and differentiation into myofibroblasts, is a major barrier to regeneration (6, 7). In these animal models, fibrosis is overcome, but the dominant role of CM proliferation complicates efforts to isolate CF’s contribution. The African spiny mouse (Acomys cahirinus), an adult mammal capable of scarless healing across multiple tissues, has emerged as a promising model to bridge this gap. In the heart, Acomys displays enhanced healing after MI, with reduced fibrosis and preserved function. Although some CM proliferation may occur, the dominant feature is a loose, afibrotic ECM (8-10). We hypothesize that CF are central mediators of the regenerative response observed in Acomys hearts. To test this, we isolated and characterized CF from Acomys and Mus, analysing their responses to pro-fibrotic biochemical (TGFβ) and mechanical stimuli. Acomys CF showed enhanced proliferation and migration, yet a blunted response to TGFβ and substrate stiffness (Fig1), with limited αSMA induction, reduced YAP nuclear translocation and less matix engagement (focal adhesions). In 3D spheroids, they produced a loose, fibronectin-rich ECM with low collagen deposition, in contrast to the dense collagen matrix formed by Mus CF (Fig2). Over time, Acomys CF showed increased matrix remodelling, particularly of collagen, while maintaining a fibronectin-rich ECM distinct from persistent thick collagen bundles produced by Mus CF. To test reversibility, we withdrew TGFβ in 3D cultures. Acomys spheroids responded with morphological changes, decreased ECM deposition, and partial loss of activation markers, supporting a dynamic and reversible fibrotic program. Moreover, Acomys CF exhibited increased apoptotic activity compared to Mus, particularly under TGFβ stimulation, suggesting a mechanism to prevent sustained fibrotic activation. These findings reveal differences in how Acomys and Mus CF respond to profibrotic stimuli, establishing a framework to: (i) better understand CF contributions to regeneration and how fibrotic traits like proliferation or migration affect outcomes; (ii) guide the development of regenerative therapies focused on ECM modulation; and (iii) gain insights into Acomys, with potential applications beyond cardiac regeneration.Figure 1For image description, please refer to the figure legend and surrounding text.  Figure 2For image description, please refer to the figure legend and surrounding text.