Researchers at the Tufts University School of Medicine and the Graduate School of Biomedical Sciences (GSBS) have unlocked a new understanding of how the human nose maintains its sensory capabilities. By utilizing a newly devised, three-dimensional model to study the regeneration of nerve tissue, the team discovered that a specific type of stem cell, long considered dormant, actually plays a pivotal, active role in preserving the sense of smell. This finding challenges previous assumptions in neurobiology and provides a promising new avenue for addressing olfactory dysfunction.
Unlike most neurons in the central nervous system, which are notoriously difficult to repair once damaged, the sensory neurons located in the nasal cavity possess a remarkable, lifelong ability to regenerate. This continuous renewal process allows the nose to recover from the near-constant barrage of environmental hazards, toxins, and pathogens it encounters daily. However, this regenerative capacity is not infinite. Viral infections—most notably the profound anosmia associated with COVID-19—as well as long-term exposure to environmental pollutants and the natural process of biological aging, can severely impair this cellular replication. When these regenerative mechanisms falter, the result is often a partial or complete loss of smell, a condition that can have significant impacts on an individual’s quality of life, nutritional intake, and safety.
To better understand the cellular machinery behind this renewal, and to pinpoint why it fails in cases of chronic disease or aging, the Tufts research team developed an innovative, accessible 3D olfactory tissue mouse model, or organoid. The study, which was recently published in the journal Cell Reports Methods, provides a granular look at the intricate communication network between two primary populations of stem cells in the nose: horizontal basal cells (HBCs) and globose basal cells (GBCs).
For years, the scientific consensus tended to categorize HBCs as largely dormant, "reserve" cells that only emerged during extreme circumstances to repair catastrophic tissue damage. However, the findings from this new model suggest a far more nuanced reality.
"Our research suggests that these two stem cells may be interdependent," explains Brian Lin, senior author of the study and a research assistant professor in the Department of Developmental, Molecular and Chemical Biology at Tufts. "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."
By utilizing their 3D organoid model, the researchers identified a distinct subpopulation of HBCs, characterized by the production of the KRT5 protein. These cells were shown to be active participants in the generation of new olfactory neurons. When the team selectively depleted these KRT5-positive HBCs from the organoid cultures, the system’s ability to generate new neurons was significantly impaired, confirming that these cells are essential architects of the regenerative process rather than mere passive bystanders.
The research also delved into the impact of the aging process on these cellular mechanisms. By growing olfactory tissue from mice of varying ages within the 3D model, the team observed a clear decline in the regenerative capacity of cells derived from older subjects. "We found a decline in the ability of the older mice cells to generate new neurons," Lin notes. "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 Development of an Accessible Research Tool
A critical component of this study was the intentional design of the model itself. The lead author, Juliana Gutschow Gameiro—a former visiting Ph.D. student at GSBS who joined the team from the State University of Londrina in Brazil—was driven by the goal of creating a system that would be accessible to laboratories regardless of their funding or equipment constraints.
The urgency for such a tool has never been greater. The global surge in olfactory loss linked to the COVID-19 pandemic, coupled with the growing awareness of smell loss as an early clinical marker for neurodegenerative conditions like Parkinson’s disease, has led to an influx of researchers entering the field. Scientists from diverse disciplines, many of whom may not be specialized stem cell biologists, are now investigating the olfactory epithelium to understand the mechanisms of nerve loss and repair.
"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," Lin says. The 3D organoid acts as a simplified, yet highly effective, proxy for the complex nasal environment, allowing for rapid experimentation that would be both costly and technically difficult in whole-animal studies.
Moving Toward Human Organoid Therapy
The successful validation of the mouse-tissue model is viewed by the team as a foundational step toward the ultimate objective: the development of a human-derived olfactory organoid. Such a model would be an invaluable tool for pharmaceutical research, enabling high-throughput drug screening to identify compounds that could restore or protect the sense of smell in patients suffering from permanent or long-term sensory loss.
Organoids have already transformed pre-clinical research for other vital organs, including the lungs and kidneys, by providing a human-centric alternative to animal models. However, creating a functional human olfactory organoid presents a unique set of technical hurdles. Unlike the mouse model, where cellular populations are easily categorized, obtaining pure olfactory tissue from human subjects is a delicate procedure.
Current methods involve a professional performing a specialized swab of the deep nasal cavity—a process similar to, but more extensive than, the standard nasal testing used for COVID-19. Once collected, the sample often contains a mixture of both respiratory and olfactory stem cells, which are notoriously difficult to isolate from one another. Because these cell types are so closely integrated in the human nasal passage, separating them without compromising the viability of the olfactory cells remains a significant engineering challenge.
The Tufts research team is now focused on overcoming this technical barrier. Their next objective is to refine a simple, cost-effective technique that can reliably isolate human olfactory stem cells from these mixed samples and coax them to proliferate in a laboratory setting. If successful, this advancement would represent a major leap forward in regenerative medicine. By bridging the gap between basic stem cell biology and clinical application, the researchers hope to transform the understanding of how the nose heals, potentially opening the door to new therapies that can restore one of the most vital, yet often overlooked, human senses. As the team continues to refine their 3D model, the focus remains on transforming these cellular discoveries into practical, life-changing interventions for patients worldwide.
