Why do corneal alkali burns trigger neovascularization? single-cell mapping reveals an amplified VEGF communication network

Why can a chemical eye injury continue to worsen long after the initial burn, leading to corneal opacity, abnormal blood vessel growth, and even vision loss? The danger of corneal alkali burns lies not only in the rapid tissue penetration of alkaline agents, but also in their ability to disrupt the cellular cooperation required for corneal repair. A new study published in Eye Discovery by researchers from the Eye Institute of Shandong First Medical University and collaborating institutions uses single-cell RNA sequencing to map how corneal and limbal tissues respond to alkali injury, revealing a multicellular disease process centered on amplified VEGF signaling.

Under healthy conditions, corneal transparency depends on a finely balanced ecosystem of limbal stem cells, transient amplifying cells, epithelial cells, stromal keratocytes, immune cells, and vascular-associated cells. Alkali injury disrupts this balance. The study identified major corneal cell populations, including limbal stem cells, transient amplifying cells, basal and differentiated epithelial cells, conjunctival epithelial cells, keratocytes, neutrophils, monocyte–macrophages, T cells, Schwann cells, vascular endothelial cells, and smooth muscle cells. After injury, both the abundance and transcriptional state of these cell types changed markedly, indicating broad remodeling of the corneal microenvironment.

One of the central findings concerns limbal stem cells, which are essential for corneal epithelial renewal. Although the injured cornea showed an apparent increase in limbal stem cell numbers, these cells displayed signs of functional compromise. Pathways associated with stemness and self-renewal, including Hippo-related signaling, were suppressed, while apoptosis, cell-cycle stress, and TNF-associated inflammatory signaling were activated. This suggests that numerical expansion does not necessarily translate into regenerative competence after alkali injury.

Transient amplifying cells, which normally help drive epithelial repair, also adopted a maladaptive state. They expanded after injury but showed increased expression of pro-apoptotic genes such as Casp3 and Bax, alongside pro-angiogenic mediators including Vegfa, Vegfd, Pgf, and Hif1a. In other words, these cells appear to be pushed into a state of abnormal proliferation, premature apoptosis, and angiogenic signaling. This may help explain why alkali-burned corneas often show both failed epithelial repair and excessive vascular growth.

The stromal and immune compartments were also strongly activated. Keratocyte subsets showed upregulation of angiogenesis-related programs and inflammatory pathways such as NF-κB and TNF signaling. Differentiated epithelial cells expressed chemokines, cytokines, inflammasome-related genes, and other immune mediators. Monocyte–macrophages displayed HIF-1 signaling, metabolic reprogramming, and increased Vegfa expression, while neutrophils showed heightened inflammatory effector programs, including Tnf, Il1b, Cxcl2, and Ccl4. These findings place inflammation and angiogenesis within the same injury-driven network rather than treating them as separate events.

Vascular endothelial cells provided the downstream evidence of pathological angiogenesis. After alkali burn, endothelial cells showed increased cell-cycle activity, DNA replication, and transcriptional reprogramming, with elevated expression of genes such as Cdk1, Cdk6, Ccna2, Ccnb1, Mcm2, and Mcm5. Cell–cell communication analysis further showed that VEGF signaling was markedly amplified in injured corneas. In normal corneas, VEGF signals were mainly predicted to arise from keratocytes and transient amplifying cells. After alkali injury, limbal stem cells and monocyte–macrophages emerged as additional VEGF signal senders, forming a broader pro-angiogenic communication network directed toward endothelial cells.

The study’s significance lies in reframing corneal alkali burn as a coordinated failure of tissue regeneration and vascular control. The findings suggest that future therapy may need to go beyond single-factor intervention. More effective strategies may require restoring limbal stem cell function, preserving the reparative capacity of transient amplifying cells, modulating macrophage and neutrophil-driven inflammation, and preventing excessive VEGF-mediated endothelial activation. At the same time, the conclusions are based primarily on single-cell transcriptomic and computational analyses, so key mechanisms and therapeutic targets will still require direct experimental validation.

The complete study is accessible Via https://doi.org/10.1016/j.edisc.2026.100028

About Eye Discovery

Eye Discovery is an open-access, peer-reviewed international academic journal, with ISSN 3117-4167. It is published quarterly by Elsevier and serves as the official journal of Eye & ENT Hospital of Fudan University, China. 

Eye Discovery  is dedicated to creating a high-end platform for ophthalmologists, scientists, and scholars worldwide to focus on innovative achievements in ophthalmology and interdisciplinary fields, and to promote academic dissemination and exchange.

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