Discovery of stem cell populations and molecular mechanisms that sustain adult meibomian glands

(Image Credit: AdobeStock/pinkeyes)

A team of researchers from Mount Sinai in New York led by coauthors Xuming Zhu, PhD, and Mingang Xu, PhD, discovered stem cell populations and molecular mechanisms that sustain the adult meibomian glands and are altered during the course of aging and in human disease. They also uncovered the hedgehog (Hh) cell-cell signaling pathway, which they noted, “is broadly important in development and disease, as a key regulator of meibomian gland stem cell proliferation and tissue regeneration. These new observations, they explained, may lead to new treatment options for dry eye disease.¹

The coauthors are from the Black Family Stem Cell Institute, the Institute for Regenerative Medicine, and the Department of Cell, Developmental and Regenerative Biology, all of the Icahn School of Medicine at Mount Sinai, New York.

Meibomian glands are critical to the ocular health in that they secrete lipid-rich meibum, which protects the ocular surface by preventing tear film evaporation. Over time, meibomian glands shrink and/or have reduced numbers of acini in humans and mice. Atrophy of these glands is associated with evaporative dry eye disease, which can result in severe vision loss and for which there is no effective therapy.^2-4

The investigators explained that meibomian gland dropout involves decreased activity of meibomian gland epithelial stem cells that normally maintain the gland through self-renewal and yielding differentiating progeny.^5-9 However, the identities of the stem cells, the nature of their supporting niche environment, and the mechanisms that control their functions in homeostasis and aging are poorly understood,¹⁰ Zhu and Xu said.

Mt. Sinai announced in a recent press release that the researchers found that increased Hh signaling is a hallmark of human meibomian gland carcinoma and that aged glands show both decreased Hh signaling and epidermal growth factor receptor (EGFR) signaling, along with impaired innervation and loss of collagen in niche fibroblasts, suggesting that changes in both glandular epithelial cells and their surrounding microenvironment contribute to age-related degeneration. These discoveries suggest that targeting Hh and EGFR signaling to stimulate stem cell activity in the meibomian glands could be a potential therapeutic option to treat evaporative dry eye disease.

Senior study author Sarah E. Millar, PhD, Dean for Basic Science of the Icahn School of Medicine at Mount Sinai, the Lillian and Henry M. Stratton Professor of Gene and Cell Medicine, Director of the Institute for Regenerative Medicine, and Director of the Black Family Stem Cell Institute, said, “We hope that our work will eventually result in new, more effective therapies for this very common condition.”

Animal study

The study used a mouse model system because the murine meibomian glands are similar in structure to human meibomian glands and, like the human glands, display decreased size and a reduced number of secretory cells in aging. The investigators carried out single nuclear RNA sequencing, in vivo lineage tracing, ex vivo live imaging, and genetic gain- and loss-of-function studies. They also analyzed gene expression in normal human eyelid samples and in human meibomian gland carcinoma.

Preclinical studies are planned to determine whether small molecules that activate Hh and EGFR signaling can rescue age-related meibomian gland degeneration, Millar said. Researchers from the Johns Hopkins University, University of Michigan, and University of Pennsylvania contributed to this study.

References

1. Zu X, Xu M, Portal C, et al. Identification of Meibomian gland stem cell populations and mechanisms of aging. Nat Commu. 2025;16:1663. https://doi.org/10.1038/s41467-025-56907-6

2. Sun M, Moreno IY, Dang M, Coulson-Thomas VJ. Meibomian gland dysfunction: what have animal models taught us?Int J Mol. Sci. 2020;21:33233466.

3. Jester JV, Parfitt GJ, Brown DJ. Meibomian gland dysfunction: hyperkeratinization or atrophy? BMC Ophthalmol. 2015;15:156.

4. Obata H. Anatomy and histopathology of human meibomian gland.Cornea. 2002;21:S70–S74.

5. Zakrzewski W, Dobrzynski M, Szymonowicz M, Rybak Z. Stem cells: past, present, and future. Stem Cell Res Ther. 2019;10:68.

6. Clevers H, Watt FM. Defining adult stem cells by function, not by phenotype.Annu Rev Biochem. 2018;87:1015–1027.

7. Nien CJ, Massei S, Lin G, et al. Effects of age and dysfunction on human meibomian glands.Arch Ophthalmol. 2011;129:462–469.

8. Hwang HS, Parfitt GJ, Brown DJ, Jester JV. Meibocyte differentiation and renewal: Insights into novel mechanisms of meibomian gland dysfunction (MGD).Exp Eye Res. 2017;163:37–45.

9. Nien CJ, Paugh JR, Massei S, et al. Age-related changes in the meibomian gland.Exp Eye Res. 2009;89:1021–1027.

10. Parfitt GJ, Lewis PN, Young RD, et al. Renewal of the holocrine meibomian glands by label-retaining, unipotent epithelial progenitors.Stem Cell Rep. 2016;7:399–410.