FGF10 is essential for postnatal meibomian gland development in mice

Abstract

Fibroblast growth factor 10 (FGF10) plays a critical role in ocular surface homeostasis, yet its function in early meibomian gland (MG) development remains largely unknown. Here, we generated an Fgf10 mutant mouse model with deletion of exon 2, leading to loss of function. Adult Fgf10+/− mice exhibited lacrimal gland agenesis, smaller Harderian glands, increased corneal fluorescein staining, and reduced tear volume. Histological analysis revealed multilayered hyperplastic epithelium in Harderian glands and MG atrophy. Time-series Oil Red O staining showed shorter, thinner, and disordered MGs in Fgf10+/− mice at P14 and P21, with unrecoverable defects at P135. RNA sequencing of MGs at P14 and P21 revealed significant dysregulation of macrophage-related genes and immune-related pathways, including antigen processing and presentation and macrophage chemotaxis. Using Cx3cr1GFP/+ reporter mice, we observed a significant reduction in CX3CR1-positive cells in the inter-acinar stroma of Fgf10+/− MGs. Pharmacological ablation of CSF1R-expressing cells with PLX3397 in wild-type mice recapitulated the MG developmental defects, confirming that FGF10 acts through immune cells to regulate MG development. Collectively, our findings establish that FGF10 haploinsufficiency leads to severe glandular malformations, impaired tear production, and compromised corneal integrity, highlighting the essential role of FGF10 in postnatal MG development and immune cell regulation.

1. Introduction

The important role of fibroblast growth factor 10 (FGF10) in the ocular surface has attracted substantial attention from researchers over the past two decades [1–3]. Its receptor, FGFR2, maintains meibomian gland (MG) homeostasis by regulating Krt5+ basal progenitors in the adult stage, and the deletion of Fgfr2 causes aberrant meibocyte differentiation, leading to ductal hyper-stratification, luminal occlusion, and secondary acinar atrophy due to impaired meibocyte renewal. However, the detailed function of FGF10 in the early development of MG remains largely unknown.

To systematically assess the impact of FGF10 on the ocular surface, our group generated an Fgf10 mutant mouse model with the removal of its entire exon two, leading to loss of function of Fgf10 in mice (Figure 1A). Adult Fgf10+/– mice exhibited lacrimal gland agenesis and possessed smaller Harderian glands than their wild-type littermates (Supplementary Figure S1A). We also evaluated tear production and corneal integrity. Fgf10+/– mice displayed a marked increase in corneal fluorescein staining and significantly reduced tear volume, indicative of epithelial damage (Supplementary Figure S1B,C). The body weights of Fgf10+/– mice were comparable to those of wild-type controls (Supplementary Figure S1D). Histological analysis further revealed that while the Harderian gland alveoli in wild-type mice were lined by a single epithelial layer, those in Fgf10+/– mice displayed a multilayered, hyperplastic epithelium (Supplementary Figure S1E). The loss of function of Fgf10 has been previously reported to lead to lacrimal gland development failure and atrophy of the Hadrian gland. Interestingly, we also observed MG atrophy in Fgf10+/– mice (Figure 1B).