The key to dormant nose cells is to keep the odors as they age

Tufts University scientists have found that once considered inactive stem cells play a crucial role in preserving our sense of smell throughout our lives.

Using a new three-dimensional tissue model, the researchers found that horizontal basal cells (HBCs) (foreseeably dormant) actively support the production of odor-induced neurons in the nose. The discovery could lead to new treatments for people who lose their sense of smell due to 19 years of age, aging or other damage to their sense of smell.

The ability of two-way partnership smells restored

Unlike most nerve cells in the brain and spinal cord, the nasal cavity contains a significant tissue that can be regenerated continuously throughout a lifetime. This regeneration depends on the two types of stem cells working together in a way that scientists have not yet fully understood until now.

“Our study shows that the two stem cells may be interdependent,” said Brian Lin, senior author of the study and an assistant professor of research in the Department of Molecular and Chemical Biology. “One type we think is largely dormant – HBC, may actually play a crucial role in supporting the production of new neurons and repairing the production of damaged tissue.”

The team developed a mouse tissue model that mimics how odor neurons in the nose develop. The organ system allows them to study the complex relationship between horizontal basal cells and spherical basal cells (GBCs) under laboratory conditions.

KRT5 Discovery

One of the most important findings of the study involved a specific subpopulation of HBCs, which produces the protein KRT5. These special cells not only sit quietly—they actively orchestrate the formation of new olfactory tissue.

When the researchers selectively deleted these KRT5-positive HBCs from their tissue cultures, production of new odor neurons was significantly impaired. The experiment shows that these alleged dormant cells are actually essential participants in the regeneration process.

This discovery challenges the traditional view that HBCs only become active after severe injuries. Instead, it shows that they are constantly working behind the scenes to maintain our scent capabilities.

Age-related decline patterns

“We also looked at cells from mice of different ages and planted them in the model,” Lin said. “We found that older mice’s cells had a decline in their ability to produce new neurons. We thought this was due to age as GBCs age, but we needed to do more work to test this hypothesis, and if so, methods to rejuvenate them.”

The researchers tested the tissues of mice from 3 to 52 weeks old. Young mice at 3 weeks produced much more neurons than older animals, and the decline in regeneration capacity decreased particularly after 6 weeks.

This age-related pattern reflects what happens in humans, where odors often worsen over the years ahead. The study shows that this decline occurs because over time, gloglycosal basal cells become fewer and less efficient.

Key findings about odor regeneration

• Contact dependencies: HBC supports odor neuron production through direct cellular contact and chemical signaling
• Niche function: HBC creates a supportive environment for GBC to thrive and distinguish
• Age sensitivity: Younger tissues produce more news neurons than older tissues
• Protein labeling: KRT5-positive HBC is crucial for organ formation and neuronal production

Molecular signal network

This study reveals complex molecular communications between two stem cell types. Using advanced computational analysis of gene expression patterns, the researchers identified several key signaling pathways that coordinated the regeneration process.

Three prominent signal pairs emerged: Midkine-syndecan4, Semaphorin3D-Neuropilin2 and Kitl-Kit. These molecular dialogues help maintain the delicate balance required for continuous odor neuron production.

Midkine signaling promotes the maintenance and growth of neural stem cells, while the Semaphorin pathway guides neurodevelopment and repair. The suite signaling system regulates stem cell behavior and affects cell self-renewal or development into specialized neurons.

Break down technical barriers

Juliana Gutschow Gameiro, the lead author of the visit to Tufts from Brazil, works to create a model that is easy to use in a lab with limited resources. The COVID-19 pandemic has sparked a widespread interest in odor research, but many laboratories lack expensive equipment or expertise.

“Because the loss of smell is associated with Covid-19 and Parkinson’s disease and other diseases, many researchers from a variety of different fields have begun to study olfactory epithelial cells over the past few years,” Lin said.

“We wanted to develop an easy-to-use model so that non-stem cell biologists and those working in laboratories with limited resources can better understand how olfactory neurons regenerate and what happens that lead to a total reduction or complete failure of the process,” he said.

From mouse to human application

The ultimate goal involves adapting this mouse model to human tissues to screen for potential treatments for odor disorders. However, using human olfactory tissue presents unique challenges.

Human tissue samples require an invasive collection procedure similar to COVID-19 testing, during which the brush is placed deep into the nasal cavity. Unlike mouse tissues, human samples contain a mixture of respiratory and olfactory stem cells that are difficult to separate.

“Getting pure olfactory tissue from humans is a challenge,” Lin said. The next challenge for the research team is to develop simple, cost-effective technologies to isolate human olfactory stem cells and encourage them to grow in laboratory conditions.

Therapeutic significance

Why is this study important for people who lose their sense of smell? The results suggest that successful treatments may need to target two stem cell populations rather than focusing only on one type.

Many current treatments for odor loss focus on reducing inflammation or protecting existing neurons. This study suggests that activating dormant HBC populations or restoring their support functions may be equally important.

Age-related findings also suggest that treatments tailored to young patients may be required as potential regenerative machinery changes over time.

Beyond odor recovery

The implications of this study go beyond odor disorders. The nose represents one of the few places in the adult nervous system where new neurons continue to form throughout their lives. Understanding this process can inform the treatment of other neurological diseases.

The organ model provides a platform for testing how various toxins, infections or drugs affect the development of odor neurons. This can help identify environmental factors that impair olfactory function or discover compounds that enhance regeneration.

This work also demonstrates that so-called inactive stem cells play a crucial auxiliary role in tissue maintenance, a principle that may apply to stem cell populations in other organs.

As researchers continue to refine the model and adapt it to human tissues, dormant cells in the nose may occupy the key to recover one of our most basic senses, the ability to smell the world around us.