Emerging research from a team led by Zhu, Chen, Ling, and colleagues, soon to be published in Nature Communications, unveils a groundbreaking mechanistic insight into the progression of myopia, a prevalent global vision disorder. Their investigation highlights the critical role of a specialized subpopulation of scleral fibroblasts expressing high levels of Wnt5a (denoted as Wnt5a^hi fibroblasts) in maintaining extracellular matrix (ECM) homeostasis within the sclera—the fibrous outer layer of the eye. This intricate cellular and molecular interplay appears to be pivotal in modulating ocular growth, with direct implications for myopic degeneration.
Myopia, commonly known as nearsightedness, has reached epidemic proportions worldwide, often leading to sight-threatening complications such as retinal detachment and glaucoma. Yet, despite its widespread prevalence, the cellular and molecular pathways dictating scleral remodeling, which ultimately drives axial elongation in myopia, have remained insufficiently understood. This study breaks new ground by characterizing the decline of Wnt5a^hi fibroblasts as a pathological event that disrupts ECM homeostasis and accelerates myopic progression.
Through rigorous experimentation conducted in murine myopia models, the researchers identified a marked reduction in Wnt5a^hi fibroblasts within the sclera of myopic eyes. Utilizing advanced single-cell transcriptomic profiling, they revealed that these fibroblasts possess a unique gene expression signature that governs ECM synthesis, turnover, and remodeling. The diminished presence of this fibroblast subset correlates strongly with altered ECM composition, characterized by decreased collagen deposition and increased matrix metalloproteinase activity, collectively undermining scleral biomechanical integrity.
At the molecular level, Wnt5a operates as a non-canonical Wnt signaling ligand, orchestrating pathways that regulate cytoskeletal dynamics, cell adhesion, and gene transcription pivotal for fibroblast function. The team’s data suggest that reduced Wnt5a signaling within scleral fibroblasts precipitates a breakdown in regulatory mechanisms responsible for ECM homeostasis. This phenomenon leads to pathological scleral thinning and increased scleral compliance, biomechanical changes that facilitate excessive axial elongation—a hallmark of progressive myopia.
The study employed a combination of genetic ablation models and gain-of-function approaches to manipulate Wnt5a expression in scleral fibroblasts. Mice with targeted depletion of Wnt5a in these cells exhibited exacerbated myopic phenotypes under visual form deprivation conditions, including pronounced axial elongation and refractive error shifts. Conversely, exogenous supplementation of Wnt5a partially ameliorated these effects, restoring ECM balance and stabilizing ocular dimensions. These causative findings underscore the therapeutic potential of Wnt5a signaling modulation.
Furthermore, the research elucidates the cellular crosstalk within the scleral microenvironment, demonstrating how Wnt5a^hi fibroblasts coordinate with neighboring cells such as fibroblast progenitors and immune cells to sustain ECM equilibrium. Disruption of this interplay under myopic stimuli compromises the tissue’s ability to withstand mechanical stresses imposed by intraocular pressure and visual stimuli, thereby fostering maladaptive scleral remodeling.
This work also integrates biomechanical assessments demonstrating that scleral tissue from mice deficient in Wnt5a^hi fibroblasts exhibits reduced stiffness and altered viscoelastic properties. These material changes potentiate ocular elongation by lessening scleral resistance to stretch forces. The findings illuminate how cellular-level molecular events cascade into tissue-level biomechanical alterations, offering a comprehensive view of myopia pathogenesis from molecule to organ.
Importantly, this study bridges a critical gap by linking a molecular signature—Wnt5a activity—to functional fibroblast behavior that directly controls ECM composition and scleral biomechanics. This linkage opens avenues to explore novel molecular targets for myopia control. Traditional interventions, chiefly optical corrections and lifestyle modifications, do not address underlying scleral biomechanics; pharmacological manipulation of Wnt5a or its downstream effectors may revolutionize future therapeutic approaches.
In addition to its biological insights, the research offers methodological advancements, showcasing the integration of single-cell RNA sequencing, immunohistochemistry, and biomechanical testing in a unified framework for ocular tissue analysis. This multidisciplinary strategy provides a robust platform for dissecting the diverse cellular populations and molecular circuits operative in complex connective tissues like the sclera.
While the study focuses on murine models, its translational relevance to human myopia is compelling given the conserved nature of Wnt signaling pathways and fibroblast biology across mammals. The authors advocate for subsequent investigations in human tissue samples and clinical cohorts to validate the presence and functional status of Wnt5a^hi fibroblasts in myopia patients, potentially enabling biomarker identification and precision medicine applications.
Moreover, the research hints at the dynamic adaptability of scleral fibroblasts in response to altered visual environments, emphasizing the plasticity of ocular connective tissue in health and disease. By delineating the molecular deficits underpinning maladaptive remodeling, the team provides a conceptual framework to understand how environmental and genetic factors converge on scleral cells to drive pathological myopia.
This pivotal study not only deepens the fundamental biological understanding of myopia progression but also exemplifies the power of molecular cell biology in addressing ocular disorders previously treated primarily by optical strategies. As global myopia rates rise, such insights could catalyze the development of next-generation therapeutics aimed at halting or reversing scleral remodeling and hence myopia progression.
In conclusion, the identification of decreased Wnt5a^hi fibroblast populations as central contributors to pathological ECM disruption and myopia exacerbation heralds a new frontier in vision science. Targeting these fibroblasts or their molecular pathways holds the promise of innovative, mechanism-driven myopia interventions. The study by Zhu and colleagues thus marks a significant leap in ocular biology, bridging cellular dynamics, molecular signaling, and tissue biomechanics to confront a pressing global health challenge.
Subject of Research: The role of Wnt5a^hi scleral fibroblasts in extracellular matrix homeostasis and myopia progression in mice
Article Title: Decreased scleral Wnt5a^hi fibroblasts exacerbate myopia progression by disrupting extracellular matrix homeostasis in mice
Article References:
Zhu, H., Chen, W., Ling, X. et al. Decreased scleral Wnt5a^hi fibroblasts exacerbate myopia progression by disrupting extracellular matrix homeostasis in mice. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67246-x
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