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Kocak G, Korsgen ME, Amores LF, Sun C, Ceylan M, Ghazwani A, Kandirici M, Zatyka M, Seranova E, Acharjee A, Barrett T, Yuksel B, Mardinoglu A, Güven S, Sarkar S
Stem Cell Reports 21 (1) 102744 [2026-01-13; online 2025-12-18]
Lacrimal glands (LGs) serve as pivotal exocrine glands crucial for protecting the ocular surface. Dysfunction in LG cell composition or secretion is implicated in dry eye disease (DED). While autophagy plays a vital role in tissue homeostasis in many organs, how it affects LG development and secretory function is not known. Here, we have undertaken a genetic study by utilizing autophagy-deficient human embryonic stem cells (hESCs) and differentiating them into LG-like organoids. Autophagy-deficient LG-like organoids exhibited improper development and secretion, along with increased protein aggregation, proliferation, and cell death. These phenotypes were associated with an accumulation of PAX6, a transcription factor crucial for brain and eye development, which we identified as an autophagy substrate. Pharmacological interventions with nicotinamide mononucleotide (NMN) and melatonin were able to rescue the cellular dysfunction in autophagy-deficient LG-like organoids. Together, our study highlights the role of autophagy in LG along with potential therapeutic interventions for DED.
PubMed 41418785
DOI 10.1016/j.stemcr.2025.102744
Crossref 10.1016/j.stemcr.2025.102744
pmc: PMC12925961
pii: S2213-6711(25)00348-0