综述：迈向全球眼表生物学图谱：基本原理、设计与临床应用

《Experimental Gerontology》：Commentary:Toward a Global Atlas of Ocular Surface Biology: Rationale, Design, and Clinical Applications

本文系统提出构建全球眼表生物学图谱（Atlas of Ocular Surface Biology）的宏伟计划，通过整合单细胞RNA测序（scRNA-seq）、空间转录组学、ATAC-seq等多组学技术，全面绘制眼表组织在生理与病理状态下的细胞分子图谱。该图谱将建立从基础研究到临床转化的桥梁，重点推动干眼病（DED）的分子分型（endotyping）和角膜移植排斥反应的无创监测（Rejection Risk Score），为精准眼科（precision ophthalmology）提供AI指导的诊断工具和个性化干预策略。

　　

Abstract:

The ocular surface—comprising the cornea, conjunctiva, and tear film apparatus—acts as a dynamic barrier to the external environment and is a leading site of vision-threatening disorders such as dry eye disease, keratoconus, and corneal graft rejection. Recent advances in single-cell and spatial omics now enable systematic, high-resolution profiling of this complex tissue. We propose the Atlas of Ocular Surface Biology, a global initiative modeled on the Human Cell Atlas and BRAIN Initiative, to comprehensively map all major ocular surface compartments—across health and disease—through integrative multi-omics including sc/snRNA-seq, ATAC-seq, spatial transcriptomics, and tear-fluid proteomics/metabolomics. The revised framework provides a phased clinical translation roadmap with explicit decision gates and two first-deployed use cases: (i) noninvasive tear-based endotyping of dry eye disease for mechanism-guided therapy allocation, and (ii) preclinical monitoring of corneal transplant rejection through a longitudinal tear-based Rejection Risk Score. Beyond pan-ocular efforts, the atlas will capture microenvironmental dynamics—including limbal stem-cell niches, goblet-cell gradients, tear film–microorganism interactions, environmental exposure responses (pollutants, humidity, contact lens wear), and immune surveillance at a mucosal barrier. We benchmark mainstream data-integration tools (e.g., Seurat, Harmony, MultiVI, cell2location, SpaIM, DIABLO, MOFA+) and specify quantitative guardrails (kBET, iLISI, cLISI/ARI, rare-cell recall) to ensure reproducibility, biological-signal preservation, and readiness for cross-site clinical deployment. Governed by an international, HCA-aligned consortium with open-science and ethical data-sharing principles, the Atlas will function as both a continuously evolving reference and a translational toolkit, enabling AI-guided diagnostics, molecular stratification, and personalized interventions in precision ophthalmology. This resource is intended to support global collaboration in vision science and to inform future mucosal-surface atlas efforts.

Introduction

The ocular surface—comprising the cornea, conjunctiva, and associated tear film apparatus—represents the eye’s primary interface with the external environment. This transparent, avascular tissue not only serves as a frontline barrier against mechanical, chemical, and microbial insults but also maintains an immune-privileged status that is essential for visual function. Disorders affecting this region—including dry eye disease (DED), corneal ulceration, limbal stem cell deficiency, and graft rejection following corneal transplantation—constitute major contributors to ocular morbidity worldwide. Among these, DED alone impacts an estimated 344 million individuals globally, causing chronic discomfort and visual impairment. Despite the high prevalence and clinical burden of ocular surface diseases, their cellular and molecular underpinnings remain comparatively underexplored relative to retinal or systemic conditions. Recent advances in single-cell and spatial omics technologies offer an unprecedented opportunity to interrogate the ocular surface at high resolution. These approaches now make a comprehensive ocular surface atlas feasible—a high-resolution reference map that captures cellular composition, molecular signatures, and spatial architecture across both healthy and diseased states. In this commentary, we present a proposal for such an atlas. We detail its scientific rationale, with defined clinical use cases in diagnostics and monitoring.

The Need for an Ocular Surface Atlas

Historically, the ocular surface has been framed by integrated models of epithelial renewal, mucin-rich barrier function, and lipid-stabilized tear film dynamics. Epithelial renewal has been shaped by the X–Y–Z model and limbal stem-cell localization, mucin-rich barrier function by the identification of conjunctival goblet-cell mucins and epithelial glycocalyx components, and tear film dynamics by the lipid–aqueous–mucin trilayer model. While foundational, these models lack the resolution to capture cellular heterogeneity, rare cell states, and dynamic molecular changes during disease. An atlas is needed to unify these classical concepts with modern molecular data, providing a systems-level view of ocular surface biology.

Scientific Scope and Multimodal Design

The Atlas of Ocular Surface Biologywill map the cellular and molecular landscape of all components of the ocular surface in health and disease, including:

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  Corneal epithelium, stroma, and endothelium: delineating layered organization from limbal stem cells to mature epithelium, stromal keratocyte subtypes, and endothelial cells.
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  Conjunctival epithelium and substantia propria: capturing goblet cells, conjunctival stem cells, resident immune populations, and ocular surface vasculature.
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  Limbus and stem cell niches: defining the microenvironment supporting limbal epithelial stem cells.
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  Tear film and associated glands: profiling the molecular composition of tears and the lacrimal functional unit.
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  Innervation and immune cells: mapping sensory nerves and resident immune cells that mediate barrier immunity.

The atlas will employ a multimodal design, integrating data from single-cell/nucleus RNA sequencing (sc/snRNA-seq), Assay for Transposase-Accessible Chromatin with sequencing (ATAC-seq), spatial transcriptomics, and tear-fluid proteomics and metabolomics. This integrated approach will link cellular identity with gene regulatory landscapes and spatial context.

Bridging the Atlas to Clinical Practice

Large-scale, cell-resolved atlases improve translational decision-making by aligning reproducible cellular states with disease mechanisms, biomarkers, and therapeutic targets—a paradigm already validated by the Human Cell Atlas and organ-specific efforts, including those focused on the anterior segment of the eye. Spatial transcriptomics adds indispensable anatomical context for detecting microniches, gradients, and cell–cell interactions that are lost in dissociated single-cell assays. The atlas framework is designed with two initial clinical use cases to demonstrate immediate translational impact.

Using Atlas Data to Support Predictive Diagnostics

The atlas is designed to be compatible with predictive modeling. The scale and complexity of multi-omic and imaging data necessitate computational analysis; conversely, a harmonized atlas provides a well-annotated training resource for machine-learning (ML) models that can support clinical decision-making in ophthalmology. We illustrate these pipelines in the disease-specific use cases. The Atlas of Ocular Surface Biologywill include labeled profiles of major cell types and states, which can serve as reference data for deconvoluting bulk transcriptomic or proteomic data from patient samples, such as tears or impression cytology specimens. This enables the translation of complex atlas data into actionable clinical biomarkers.

Technical and Standardization Challenges

Constructing the Atlas of Ocular Surface Biologyis an ambitious undertaking that presents several technical challenges. We address these via standardized SOPs, shared references, and cross-site QC. Key challenges include batch effect correction across multiple sequencing centers, integration of multimodal data types, and spatial mapping accuracy. The initiative benchmarks mainstream data-integration tools (e.g., Seurat, Harmony, MultiVI, cell2location, SpaIM, DIABLO, MOFA+) and specifies quantitative guardrails (kBET, iLISI, cLISI/ARI, rare-cell recall) to ensure reproducibility and biological-signal preservation.

Global Collaboration Framework

The consortium will comprise international sites with defined roles in tissue procurement, data generation, and coordination. Ocular surface diseases affect diverse populations across climates, ethnicities, and healthcare systems; capturing this variation requires globally coordinated effort. We outline a framework centered on open science, ethical compliance, and equitable participation. Governed by an international, HCA-aligned consortium, the Atlas will adhere to FAIR (Findable, Accessible, Interoperable, Reusable) data principles.

Challenges, Limitations, and Future Outlook

While the potential of the ocular surface atlas is substantial, it is important to acknowledge key challenges and outline strategies to address them. These include sample heterogeneity, computational scalability, and long-term sustainability. The atlas is envisioned as a continuously evolving resource that will incorporate new data and technologies over time.

Conclusion

The Atlas of Ocular Surface Biologyis an ambitious, timely initiative at the intersection of basic science, clinical ophthalmology, and data science. By comprehensively mapping the cellular and molecular landscape of the ocular surface, it aims to advance understanding of maintenance, immunity, and disease. The atlas will function both as a reference—cataloging cell types from limbal stem cells to conjunctival goblet cells—and as a translational toolkit, linking discoveries to diagnostics and personalized therapies in precision ophthalmology. This resource is poised to catalyze global collaboration in vision science.