Stem cells stop dividing. The tissue around them falls apart. Aging wins.
Tucked within the margins of every eyelid are tiny oil glands whose quiet labor keeps the eye's surface intact — and whose gradual failure with age leaves millions of older adults in chronic discomfort. Researchers at Mount Sinai have now traced that failure to its cellular roots, identifying the stem cell populations and signaling pathways that govern whether these glands renew themselves or quietly exhaust. Published in Nature Communications in February 2025, the findings reframe dry eye disease not as an inconvenience to be managed, but as a regenerative failure that may one day be reversed.
- Evaporative dry eye disease affects millions of older adults, yet current treatments — warm compresses, artificial tears, thermal devices — address only symptoms while the underlying gland degeneration continues unchecked.
- Using single-cell RNA sequencing and genetic tools in mouse models, Mount Sinai scientists mapped the precise stem cell populations responsible for maintaining meibomian gland structure, revealing a landscape that had remained largely uncharted.
- Two signaling pathways — hedgehog and EGFR — emerged as master regulators of gland regeneration, and both show measurably reduced activity in aged tissue, pointing directly to why the glands stop renewing themselves.
- The deterioration is compounded by a failing microenvironment: the collagen and nerve connections that support stem cells also degrade with age, creating a dual collapse of both the cells and the niche that sustains them.
- The next phase will test small molecules capable of reactivating these pathways in living systems — a preclinical step toward what could become the first treatment targeting the root cause of age-related dry eye rather than its surface effects.
The meibomian glands lining the eyelid margins perform a task so routine it goes unnoticed — secreting a lipid layer that prevents tears from evaporating too quickly. When these glands shrink with age, the result is evaporative dry eye disease: swollen lids, blurred vision, persistent irritation affecting millions of older adults. Existing remedies offer only partial relief, and the biological reasons for the glands' decline had remained poorly understood.
A research team led by Sarah Millar at Mount Sinai's Icahn School of Medicine set out to change that. Working with mouse models whose meibomian glands closely mirror human anatomy, they used single-cell RNA sequencing and genetic manipulation to map the glands' cellular architecture across age. They identified distinct stem cell populations responsible for maintaining gland structure — and discovered that two signaling pathways, hedgehog and EGFR, act as central regulators of stem cell activity and tissue renewal.
The picture that emerged was one of compounding decline. In aged glands, both pathways show reduced activity. Simultaneously, the surrounding microenvironment — the collagen scaffolding and nerve connections that support stem cells — also deteriorates. This dual erosion, of both the stem cells and the niche that sustains them, explains why aging glands lose their capacity to regenerate. A notable aside: elevated hedgehog signaling was found in meibomian gland carcinoma, underscoring the pathway's centrality to gland biology in both health and disease.
Published in Nature Communications in February 2025, the findings open a concrete therapeutic direction. If small molecules can be developed to reactivate hedgehog and EGFR signaling in aged tissue, they might restore stem cell function and reverse gland degeneration rather than merely managing its symptoms. Preclinical studies are the next step, with collaborators from Johns Hopkins, the University of Michigan, and the University of Pennsylvania involved in the broader effort.
The tiny oil glands that line your eyelids have a job most people never think about: they secrete a lipid-rich substance that coats the eye surface and keeps tears from evaporating too quickly. When those glands shrink with age, the result is a condition called evaporative dry eye disease—swollen lids, itchy eyes, blurred vision—that affects millions of older adults and resists most conventional treatments. A team of researchers at Mount Sinai has now identified why those glands deteriorate, and the answer points toward a potential fix.
The meibomian glands, as they're called, are microscopic structures embedded in the eyelid margins. In younger people, they function reliably. But aging brings shrinkage and a loss of the secretory cells that produce the protective oil. Current remedies—warm compresses, artificial tears, thermal pulsation devices—offer only partial relief. The underlying mechanism, until now, remained largely mysterious.
Working with mouse models whose meibomian glands closely resemble human ones, researchers led by Sarah Millar, Dean for Basic Science at Mount Sinai's Icahn School of Medicine, used advanced techniques including single-cell RNA sequencing and genetic manipulation to map what happens inside these glands over time. They identified distinct stem cell populations that normally maintain the gland's structure and function. More importantly, they discovered that two cellular signaling pathways—one called hedgehog signaling and another involving the epidermal growth factor receptor—act as master regulators of stem cell activity and tissue regeneration.
The findings, published in Nature Communications on February 15, revealed a striking pattern. In aged glands, both signaling pathways show reduced activity. The researchers also found that the tissue surrounding the gland cells—the microenvironment that supports them—deteriorates with age, losing collagen and nerve connections. This dual decline, affecting both the stem cells themselves and the niche they inhabit, explains why aging glands fail to regenerate. Interestingly, the team also discovered that increased hedgehog signaling is a hallmark of meibomian gland carcinoma, a rare eyelid cancer, suggesting the pathway's central importance to gland health.
The implications are concrete. If researchers can develop small molecules that reactivate hedgehog and EGFR signaling in aged glands, they might be able to restore stem cell activity and reverse the degeneration. Millar emphasized that despite dry eye disease's prevalence, the molecular mechanisms controlling meibomian gland health have been poorly understood until now. The work represents a shift from treating symptoms to addressing root cause.
The research involved collaborators from Johns Hopkins University, the University of Michigan, and the University of Pennsylvania. Next steps include preclinical studies to test whether such molecules can actually rescue aged glands in living systems. If successful, the approach could offer older adults a genuinely new therapeutic option—not a temporary palliative, but a way to restore the glands' capacity to function as they once did.
Citas Notables
Despite the prevalence of dry eye disease, the stem cells and molecular mechanisms that control homeostasis of the meibomian gland are poorly understood. We hope our work will eventually result in new, more effective therapies.— Sarah E. Millar, PhD, Mount Sinai
La Conversación del Hearth Otra perspectiva de la historia
Why does this matter beyond the people who have dry eyes? It seems like a quality-of-life issue, not a public health crisis.
It affects millions of older adults, and current treatments barely work. But more broadly, this is about understanding how stem cells fail in aging. The meibomian gland is a model system—small, accessible, well-defined. What they learn here about why stem cells exhaust and how the tissue environment deteriorates could apply to other age-related conditions.
So they're not just fixing dry eyes. They're studying aging itself.
Exactly. The gland shrinks because stem cells stop dividing and regenerating. That's a fundamental aging problem. They've identified the signaling pathways that control it. If they can reactivate those pathways, they've potentially found a lever for reversing aging in this tissue.
The hedgehog pathway—that's a strange name. What does it actually do?
It's a cell-to-cell communication system that's been around since early development. It tells cells whether to divide, differentiate, or stay put. In young glands, it's active and keeps stem cells proliferating. In old glands, it quiets down. The researchers think turning it back on could restart regeneration.
And they found it's overactive in cancer of these glands. That's a warning sign, isn't it?
It is. It suggests the pathway needs to be carefully balanced. Too little signaling and the gland degenerates. Too much and cells might become cancerous. Any therapeutic approach will have to thread that needle—stimulate regeneration without triggering malignancy.