Dormant Nose Cells Key to Keeping Smell Sharp With Age

Scientists at Tufts University have discovered that stem cells once thought to be inactive play a crucial role in preserving our sense of smell throughout life.

Using a new three-dimensional tissue model, researchers found that horizontal basal cells (HBCs)—previously considered dormant—actively support the generation of smell-sensing neurons in the nose. This finding could lead to new treatments for people who have lost their sense of smell due to COVID-19, aging, or other conditions that damage olfactory tissue.

Two-Cell Partnership Powers Smell Recovery

The nasal cavity contains a remarkable type of tissue that can continuously regenerate throughout life, unlike most nerve cells in the brain and spinal cord. This regeneration depends on two types of stem cells working together in ways scientists didn’t fully understand until now.

“Our research suggests that these two stem cells may be interdependent,” says Brian Lin, senior author on the study and a research assistant professor in the Department of Developmental, Molecular and Chemical Biology. “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 research team developed a mouse tissue model that mimics how smell neurons develop in the nose. This organoid system allowed them to study the intricate relationship between horizontal basal cells and globose basal cells (GBCs) in laboratory conditions.

The KRT5 Discovery

One of the study’s most significant findings involves a specific subpopulation of HBCs marked by their production of the protein KRT5. These particular cells don’t just sit quietly—they actively orchestrate the formation of new olfactory tissue.

When researchers selectively removed these KRT5-positive HBCs from their tissue cultures, the generation of new smell neurons was significantly impaired. This experiment demonstrated that these supposedly dormant cells are actually essential players in the regenerative process.

The discovery challenges the traditional view that HBCs only become active after severe injury to nasal tissue. Instead, it suggests they constantly work behind the scenes to maintain our ability to smell.

Age-Related Decline Patterns

“We also looked at cells from mice of different ages and grew them in the model,” Lin says. “We found a decline in the ability of the older mice cells to generate new neurons. We think this is due to a decrease in the GBC population as we age, but we need to do more work to test this hypothesis and if so, develop ways to rejuvenate them.”

The researchers tested tissue from mice ranging from 3 weeks to 52 weeks old. Young mice at 3 weeks generated significantly more smell neurons than older animals, with the regenerative capacity declining notably after 6 weeks of age.

This age-related pattern mirrors what happens in humans, where smell often deteriorates with advancing years. The research suggests this decline occurs because globose basal cells become less numerous and less effective over time.

Key Findings About Smell Regeneration

• Contact dependency: HBCs support smell neuron production through both direct cell contact and chemical signals
• Niche function: HBCs create a supportive environment for GBCs to thrive and differentiate
• Age sensitivity: Younger tissue generates more new smell neurons than older tissue
• Protein markers: KRT5-positive HBCs are essential for organoid formation and neuron production

Molecular Signaling Networks

The study revealed sophisticated molecular communication between the two stem cell types. Using advanced computational analysis of gene expression patterns, researchers identified several key signaling pathways that coordinate the regenerative process.

Three prominent signaling pairs emerged: Midkine-Syndecan4, Semaphorin3d-Neuropilin2, and Kitl-Kit. These molecular conversations help maintain the delicate balance needed for continuous smell neuron production.

Midkine signaling promotes neural stem cell maintenance and growth, while Semaphorin pathways guide nerve development and repair. The Kit signaling system regulates stem cell behavior and influences whether cells self-renew or develop into specialized neurons.

Breaking Down Technical Barriers

Lead author Juliana Gutschow Gameiro, who came to Tufts from Brazil, focused on creating a model that laboratories with limited resources could easily use. The COVID-19 pandemic sparked widespread interest in smell research, but many labs lacked expensive equipment or specialized techniques.

“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,” says Lin.

“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 and what happens that causes that process to diminish or fail completely,” he says.

From Mouse to Human Applications

The ultimate goal involves adapting this mouse model for human tissue to screen potential treatments for smell disorders. However, working with human olfactory tissue presents unique challenges.

Human tissue samples require invasive collection procedures similar to COVID-19 testing, where a brush is inserted deep into the nasal cavity. Unlike mouse tissue, human samples contain mixtures of respiratory and olfactory stem cells that are difficult to separate.

“It’s challenging to get pure olfactory tissue from humans,” Lin says. The research team’s next challenge involves developing simple, cost-effective techniques for isolating human olfactory stem cells and encouraging them to grow in laboratory conditions.

Therapeutic Implications

Why does this research matter for people who’ve lost their sense of smell? The findings suggest that successful treatments might need to target both stem cell populations rather than focusing on just one type.

Many current approaches to treating smell loss focus on reducing inflammation or protecting existing neurons. This research indicates that activating the dormant HBC population or restoring their supportive function could be equally important.

The age-related findings also suggest that treatments might need to be tailored differently for younger versus older patients, since the underlying regenerative machinery changes over time.

Beyond Smell Recovery

The research has implications extending beyond smell disorders. The nose represents one of the few places in the adult nervous system where new neurons continuously form throughout life. Understanding this process could inform treatments for other neurological conditions.

The organoid model provides a platform for testing how various toxins, infections, or drugs affect smell neuron development. This could help identify environmental factors that damage olfactory function or discover compounds that enhance regeneration.

The work also demonstrates how supposedly inactive stem cells can play crucial supporting roles in tissue maintenance—a principle that might apply to stem cell populations in other organs.

As researchers continue refining this model and adapting it for human tissue, the dormant cells of the nose may hold keys to restoring one of our most fundamental senses—the ability to smell the world around us.