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

Image Credits: AI Generated

Myopia, or nearsightedness, has emerged as a global epidemic, particularly afflicting populations in East and Southeast Asia. With the prevalence continuing to rise, the demand for effective myopia control measures has intensified. Orthokeratology involves the overnight wearing of specially designed contact lenses that temporarily reshape the cornea, thereby reducing axial elongation—a principal driver of myopia progression. While clinical parameters such as age and initial myopia degree have provided some guidance on who benefits most from orthokeratology, these traditional predictors fall short of fully explaining patient variability.

Increasing evidence points to the retina as a critical player in regulating eye growth and refractive development. This knowledge prompted researchers from Wenzhou Medical University’s National Clinical Research Center for Ocular Diseases, in collaboration with PSI Genomics, to investigate whether genetic differences in retinal-related genes could underpin the varied efficacy of orthokeratology. By analyzing whole-genome sequencing data from 545 children aged 8 to 12 who used orthokeratology lenses for a year, the team sought to untangle the complex genetic factors linked to treatment response.

The study employed a targeted approach focusing on genes cataloged in the RetNet database, which is known to include genes implicated in inherited retinal diseases. Initial clinical analysis confirmed that older children, those with higher spherical equivalent (SE) refractive errors, and longer baseline axial lengths exhibited better control of myopia progression under orthokeratology treatment. However, these variables alone could not account for the full spectrum of treatment outcomes observed.

Zooming in on genetic data, the researchers selected 60 children at the extremes of treatment response—those with particularly effective control of axial elongation and those with poor results. Strikingly, children benefiting most had a significantly higher number of nonsynonymous mutations—mutations that alter protein structure—in genes related to retinal development and signaling pathways. This implies that retinal genetic architecture may influence how effectively orthokeratology modulates eye growth.

Two genes, in particular, emerged as key influencers: RIMS2 and LCA5. The RIMS2 gene, more frequently mutated in poor responders, encodes a protein associated with synaptic function in rod photoreceptors, influencing contrast sensitivity. Rod photoreceptors play a crucial role in dim lighting but also participate in signaling pathways that regulate eye growth. Conversely, LCA5, enriched in the group with favorable treatment outcomes, is essential for photoreceptor maintenance, specifically in cones, which are vital for color vision and sharp central vision. Variations in this gene suggest enhanced photoreceptor support could underlie better responsiveness to corneal reshaping interventions.

Further fine-mapping identified specific single nucleotide polymorphisms (SNPs) within SLC7A14 (rs36006402) and CLUAP1 (rs2285814) that associate significantly with axial elongation rates during orthokeratology treatment. SLC7A14 is involved in amino acid transport in photoreceptors, while CLUAP1 plays a role in cilia function—both critical in maintaining retinal cellular health and signaling. These findings underscore the sensory retina’s active role in governing eye growth modulation and, by extension, treatment efficacy.

These revelations mark a pioneering implementation of genome-wide genetic profiling to explain individual variability in orthokeratology success, bridging clinical ophthalmology with molecular genetics. The study’s authors highlight the translational potential of this work to usher in precision ophthalmology, where genetic screening may one day guide clinicians in predicting who will benefit from orthokeratology before initiating treatment, thereby optimizing therapeutic outcomes.

Dr. Xinjie Mao, co-corresponding author of the study, emphasized the transformative promise of integrating genetics into myopia management. He noted that children exhibiting rapid eye growth—most at risk for sight-threatening complications later in life—might be monitored more closely or offered alternative interventions if genetic markers predict a less favorable response to orthokeratology. Such a stratified approach would minimize ineffective treatment trials and maximize resource use.

Moreover, these genetic insights could catalyze the design of next-generation orthokeratology lenses or adjunct therapies tailored to the underlying retinal biology. For example, combining low-dose atropine, a pharmacologic agent proven to slow myopia progression, with lens designs informed by a patient’s genetic profile could magnify therapeutic efficacy. This comprehensive strategy would move beyond the conventional one-size-fits-all approach, creating customized treatments that address both corneal biomechanics and retinal signaling.

While the study paves the way for the integration of genetics into clinical eye care, the authors acknowledge the necessity of larger scale, multi-ethnic cohorts to validate the predictive utility of the identified gene variants. Such expansive research will also clarify how these genetic variants interact with environmental factors, such as near-work activities and outdoor exposure, which are known contributors to myopia development.

The implications extend beyond clinical care into public health policy, particularly in countries facing a myopia crisis. Early genetic screening in pediatric populations could identify children at heightened risk for rapid myopia progression who would benefit most from early orthokeratology intervention or alternative strategies. This proactive, genetics-informed framework could play a vital role in curbing the personal and societal burdens of high myopia, including its association with retinal detachment, glaucoma, and macular degeneration.

In summary, this landmark study offers critical evidence that genetic polymorphisms in retinal-related genes significantly affect the success of orthokeratology in controlling myopia progression. By elucidating the molecular underpinnings of treatment variability, it sets the stage for a paradigm shift toward personalized, genetics-driven myopia management in pediatric ophthalmology. The convergence of genomic technologies and clinical practice holds immense promise for mitigating the global myopia epidemic through more effective, targeted interventions.

Subject of Research: Not applicable
Article Title: Associations between RetNet gene polymorphisms and the efficacy of orthokeratology for myopia control: a retrospective clinical study
News Publication Date: 17-Mar-2025
Web References: http://dx.doi.org/10.1186/s40662-025-00426-4
References: DOI: 10.1186/s40662-025-00426-4
Image Credits: Eye and Vision
Keywords: Health and medicine