While inflammation, tear film instability, and meibomian gland dysfunction dominate clinical conversations of dry eye disease (DED), lacrimal gland biology itself — particularly the molecular mechanisms governing acinar and ductal cell development — has been comparatively understudied. A new Stem Cell Reports study now brings fresh insight into this space, revealing that autophagy, a core cellular recycling pathway, is indispensable for the proper development and function of human lacrimal gland–like organoids.
Using an elegant human embryonic stem cell (hESC) model, the researchers generated self-formed ectodermal autonomous multi-zone (SEAM) structures that recapitulate early ocular development. From these, they derived three-dimensional lacrimal gland–like organoids — miniature tissue models expressing familiar markers of acinar, ductal, and myoepithelial lineages. When autophagy was genetically disabled through ATG5 knockout, the result was striking: improper lacrimal gland differentiation, reduced expression of key markers such as CK5, CK19, AQP5 and α-SMA, and a paucity of gland-like clusters. These structural abnormalities were accompanied by diminished secretory function, including markedly reduced lactoferrin, lipocalin-2, and lysozyme-associated enzyme activity.
Beyond impaired development, the autophagy-deficient organoids displayed hallmarks of cellular stress: protein aggregation, heightened proliferation, and increased apoptosis — features that mirror degenerative processes implicated in chronic DED.
Perhaps the most clinically intriguing findings arise from the study’s rescue experiments: two pharmacological agents — nicotinamide mononucleotide (NMN) and melatonin — were evaluated for their ability to restore function to autophagy-deficient organoids. Both improved aspects of secretion, but NMN alone reversed deeper cellular abnormalities, including aggresome accumulation, mitochondrial fragmentation, NAD⁺ depletion, and excessive apoptosis. The study authors propose that NMN’s ability to rebalance NAD⁺ metabolism and normalize SIRT1 activity underlies its protective effect — a mechanism with potential therapeutic implications.
While translation from organoid to clinic will require significant validation, the study provides a compelling framework for rethinking how lacrimal gland health is maintained — and how it might be restored in the future.
