These supposedly sleeping cells were doing essential work all along.
Tucked within the nasal passages lies a quiet miracle — sensory neurons that can rebuild themselves across a lifetime, even as the world assaults them with viruses, toxins, and time. Researchers at Tufts University have now illuminated a hidden architect of that renewal: a population of stem cells long believed to be dormant, which turn out to be essential partners in regenerating the neurons that let us smell. Their discovery, built from a modest laboratory-grown tissue model, reframes how science understands olfactory loss — and points toward future treatments for the millions whose sense of smell has been dimmed by COVID-19, Parkinson's disease, or the slow erosion of age.
- A stem cell type dismissed as largely inactive — horizontal basal cells — has been found to be a critical engine of smell-neuron regeneration, overturning a foundational assumption in olfactory biology.
- When researchers removed these cells from their lab-grown nasal tissue, neuron production collapsed, making the stakes of the misclassification suddenly concrete.
- Older mouse cells generated far fewer new neurons than younger ones, suggesting that age quietly depletes the stem cell populations the nose depends on — a mechanism that may explain why smell fades across a lifetime.
- The organoid model was deliberately designed to be simple and inexpensive, so that labs worldwide — including those newly drawn to olfactory research by the COVID-19 pandemic — can use it without specialized expertise or large budgets.
- The team's next frontier is a human version of the organoid, which would serve as a drug-screening platform for restoring smell lost to COVID-19, Parkinson's, and aging — though isolating human olfactory stem cells from deep within the nasal cavity remains a formidable practical challenge.
The nose holds a regenerative capacity rare in the human body — its smell-sensing neurons can renew themselves across a lifetime. But that capacity falters under the pressure of viral infection, toxic exposure, and age. To understand why, researchers at Tufts University built a three-dimensional organoid from mouse nasal cells and watched the process unfold in real time. What they found surprised them.
A class of stem cells called horizontal basal cells, long assumed to be mostly dormant, turned out to be indispensable to the whole regenerative system. Working alongside a more active stem cell type, these cells actively drive the production of new odor-sensing neurons. When the team removed them from their organoid cultures, neuron generation dropped sharply. The cells had been doing essential work in plain sight, unrecognized. The finding, published in Cell Reports Methods, was led by Brian Lin and doctoral researcher Juliana Gutschow Gameiro, who also designed the organoid to be affordable and accessible — a deliberate choice, given how many researchers across disciplines have turned to olfactory science since COVID-19.
The team also observed that cells from older mice produced fewer new neurons, hinting that aging depletes the stem cell populations the nose relies on — a possible explanation for why smell quietly fades with time, and why diseases like Parkinson's can strip it away entirely.
The larger ambition now is to build the same kind of organoid from human tissue, creating a platform to screen drugs that might restore smell to those who have lost it. The obstacle is practical: collecting human olfactory stem cells requires a delicate procedure deep in the nasal cavity, and the cells retrieved are difficult to separate from neighboring respiratory cells. If the team can solve that problem, they will have opened a path toward treatment for millions whose world has grown quieter and less fragrant — through no fault of their own.
The nose has a gift most of the body does not: its sensory neurons can rebuild themselves throughout a person's lifetime, even as they face constant assault from the outside world. But that regenerative power falters. Viral infections like COVID-19, toxic exposures, aging itself—all can dim or erase the sense of smell. Researchers at Tufts University wanted to understand why, and to do that, they needed to watch the process happen in real time.
They built a three-dimensional model of nasal tissue using mouse cells, a kind of laboratory-grown organ called an organoid. The work, published recently in Cell Reports Methods, revealed something unexpected: a type of stem cell long assumed to be mostly inactive—horizontal basal cells, or HBCs—turns out to be essential to the whole regenerative machinery. These cells work in concert with another stem cell type called globose basal cells to continuously generate new neurons that detect odor. The discovery challenges what scientists thought they knew about how smell regenerates and why that process breaks down.
Brian Lin, a research assistant professor in the Department of Developmental, Molecular and Chemical Biology at Tufts, led the team. "Our research suggests that these two stem cells may be interdependent," he said. "One type that we thought was largely dormant—HBCs—may actually play a crucial role in supporting the production of new neurons and the repair of damaged tissue." The researchers identified a specific subset of HBCs, marked by their production of a protein called KRT5, that actively drive the formation of new smell-sensing neurons. When they removed these cells from their organoid cultures, neuron generation dropped sharply. The implication was clear: these supposedly sleeping cells were doing essential work all along.
The team also grew cells from mice of different ages and watched what happened. Older cells generated fewer new neurons than younger ones. Lin suspects this decline stems from a shrinking population of globose basal cells as we age, though more research is needed to confirm that hypothesis and find ways to reverse it. The findings open a window onto why smell fades with time and why certain diseases—Parkinson's among them—rob people of this sense.
Juliana Gutschow Gameiro, a former doctoral student from Brazil who led the study, designed the organoid to be simple and cheap to make. That was deliberate. "Because loss of smell is associated with COVID-19, as well as with Parkinson's disease and other conditions, a much larger number of researchers from a variety of different fields have begun researching olfactory epithelial cells in the last few years," Lin explained. The team wanted to create a tool that researchers without deep expertise in stem cell biology—and labs without large budgets—could actually use. The mouse organoid accomplishes that.
But the real prize lies ahead. The researchers want to build the same kind of organoid using human olfactory tissue, which would allow them to test drugs that might restore smell to people who have lost it. Organoids have already been developed for lungs, kidneys, and other organs, but not for the olfactory system. The challenge is practical: extracting human olfactory stem cells requires anesthetizing a patient and inserting a brush deep into the nasal cavity—similar to a COVID test—but the cells collected this way are mixed with respiratory stem cells and difficult to separate. The team's next task is to devise a simple, affordable method to isolate the olfactory cells and coax them to grow in culture. If they succeed, they will have created a platform for screening treatments for millions of people whose sense of smell has been stolen by age, disease, or infection.
Citas Notables
One type that we thought was largely dormant—HBCs—may actually play a crucial role in supporting the production of new neurons and the repair of damaged tissue.— Brian Lin, research assistant professor at Tufts
We wanted to develop an easy-to-use model so that non-stem cell biologists and those working in labs with limited resources could use it to better understand how olfactory neurons regenerate.— Brian Lin
La Conversación del Hearth Otra perspectiva de la historia
Why does the nose regenerate neurons when most of the brain doesn't?
The olfactory epithelium sits at the boundary between the body and the outside world. It's constantly exposed to damage—viruses, toxins, particles—so evolution gave it the ability to repair itself continuously. The central nervous system doesn't have that luxury or that need.
And these HBCs were thought to be dormant. What does dormant actually mean in this context?
It means scientists thought they were there but not actively doing much—like backup cells waiting for an emergency. What this research shows is that they're actually working all the time, supporting the cells that directly generate new neurons. The dormancy was an illusion created by how we were looking at them.
Why does smell decline with age if the regenerative machinery is still there?
The team found that the population of globose basal cells—the other type of stem cell—shrinks as we get older. If you have fewer of those cells, you generate fewer new neurons, even if the HBCs are still trying to do their job. It's like having fewer workers on a production line.
What's the practical difference between a mouse organoid and a human one?
The mouse version is proof of concept. A human organoid would let researchers test drugs directly on human tissue before giving them to patients. Right now, if you want to study human olfactory cells, you have to extract them from people's noses, which is invasive and yields a messy mixture of cell types.
Why is the separation problem so hard?
When you brush the human nasal cavity, you collect both olfactory stem cells and respiratory stem cells. They're sitting right next to each other in the tissue. In mice, researchers can isolate them more easily. For humans, there's no simple, cheap way to sort them apart yet.
If they solve that, what becomes possible?
Drug screening at scale. Instead of testing compounds on whole animals or crude cell cultures, you could test them on organoids that behave like actual human olfactory tissue. That means faster development of treatments for smell loss from COVID, Parkinson's, aging—conditions that affect millions of people.