In the intricate landscape of human sensory perception, the sense of smell often operates as a silent sentinel, anchoring our memories, warning us of environmental hazards, and enriching the basic experience of eating. Yet, despite its importance, the mechanisms by which the body maintains and repairs the delicate nerve tissue responsible for olfaction have remained partially shrouded in mystery. Now, a breakthrough study led by researchers at the Tufts University School of Medicine and the Graduate School of Biomedical Sciences (GSBS) has shed new light on this process, utilizing a sophisticated three-dimensional model to uncover the hidden dynamics of nasal tissue regeneration.
The research, recently published in the journal Cell Reports Methods, challenges long-held assumptions about the stem cells residing in the nasal cavity. Specifically, the team discovered that a type of stem cell previously thought to be largely dormant—the horizontal basal cell (HBC)—actually plays a far more active and essential role in preserving the sense of smell than the scientific community had originally believed. By developing a new, accessible "organoid" model, the researchers have provided a powerful tool for understanding how the nose heals itself and why this vital capacity often falters with age or disease.
The Unique Regenerative Power of the Nose
To appreciate the significance of the Tufts study, one must first understand the unique biological environment of the nasal cavity. Unlike the central nervous system, where neurons are notoriously difficult to replace once damaged, the olfactory system possesses a remarkable and near-constant ability to regenerate. The sensory neurons in the nose are essentially the only part of the nervous system that is directly and continuously exposed to the external world. Every breath brings a barrage of potential insults, including viral pathogens, environmental toxins, pollutants, and physical trauma.
To survive this constant exposure, the body has evolved a robust regenerative engine within the olfactory epithelium—the specialized tissue lining the nasal cavity. Throughout a person’s life, new neurons are born, mature, and integrate into the existing neural circuitry, replacing those that have died or been damaged. However, this process is not invincible. Factors such as aging, chronic exposure to toxins, or severe viral infections—most notably seen in the global experience of COVID-19—can diminish the function of these cells or strip away their ability to replicate. This failure of the regenerative cycle often results in hyposmia (a diminished sense of smell) or anosmia (the total loss of smell), conditions that can profoundly impact quality of life and mental health.
Unmasking the "Dormant" Stem Cell
The engine of this regeneration is driven by two primary types of stem cells: horizontal basal cells (HBCs) and globose basal cells (GBCs). For years, the prevailing scientific consensus was that GBCs were the primary "workhorses" of the system, actively dividing and differentiating into new neurons. In contrast, HBCs were viewed as a sort of emergency reserve—dormant cells that only sprang into action in response to catastrophic tissue damage.
The Tufts research team, led by senior author Brian Lin, a research assistant professor in the Department of Developmental, Molecular and Chemical Biology, has now overturned this "dormant" label. Using their newly devised 3D mouse model, the team observed that these two cell types do not operate in isolation. Instead, they exist in a state of complex interdependency.
"Our research suggests that these two stem cells may be interdependent," explains Lin. "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 closely monitoring the behavior of these cells within the 3D organoid, the researchers identified a specific subpopulation of HBCs characterized by the production of a protein known as KRT5. These KRT5-positive cells were found to be actively involved in supporting the generation of new olfactory neurons. When the researchers experimentally depleted these specific HBCs from the organoid cultures, the results were striking: the generation of new neurons was significantly impaired. This finding suggests that HBCs are not merely a backup system but are essential players that provide the necessary environment and signals for the GBCs to function correctly.
The Impact of Aging on Sensory Health
Beyond identifying the roles of specific cell types, the study also delved into the inevitable decline of sensory function associated with getting older. It is a common clinical observation that the sense of smell weakens as people age, yet the underlying cellular causes have been difficult to pin down.
Using their organoid model, Lin and his colleagues compared cells harvested from young mice with those taken from older subjects. The 3D cultures provided a clear window into the aging process. They observed a marked decline in the ability of cells from older mice to generate new neurons compared to their younger counterparts.
"We found a decline in the ability of the older mice cells to generate new neurons," Lin says. The team hypothesizes that this decline is linked to a diminishing population of globose basal cells (GBCs) as the organism ages. While the HBCs may still be present, the overall "pool" of active progenitor cells seems to shrink or become less efficient over time. "We need to do more work to test this hypothesis and if so, develop ways to rejuvenate them," Lin adds, pointing toward a future where age-related sensory loss might be reversible.
An Easy-To-Use Model
One of the most significant contributions of this study is the model itself. In the world of modern biology, researchers often rely on organoids—miniaturized, simplified versions of organs grown in a lab that mimic the three-dimensional architecture and biological function of real tissue. While organoids have been successfully developed for the lungs, kidneys, and intestines, the olfactory system has proven more elusive.
The lead author of the study, Juliana Gutschow Gameiro, played a pivotal role in designing a model that was not only effective but also accessible. A former Ph.D. student visiting the Graduate School of Biomedical Sciences at Tufts from the State University of Londrina in Brazil, Gameiro was dedicated to the idea of "democratizing" this research. She worked to develop a 3D olfactory tissue model that was easy to create, even for laboratories that might lack the massive funding or specialized equipment often required for high-end stem cell research.
The timing of this development is critical. In the wake of the COVID-19 pandemic, interest in olfactory research has exploded. Millions of people worldwide experienced a loss of smell as a primary symptom of the virus, and for many, the sense has not fully returned. This has drawn researchers from disparate fields—neurology, immunology, and geriatrics—to study the nasal cavity.
"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."
Next Step: A Human Organoid
While the current mouse-tissue model has provided groundbreaking insights, the Tufts team views it as a stepping stone toward a more ambitious goal: the creation of a human olfactory organoid. Such a model would be a game-changer for clinical medicine, providing a platform to screen drugs and develop therapies for patients suffering from permanent smell loss.
In the pharmaceutical industry, organoids represent a major leap forward. They allow for pre-clinical trials that are faster, less expensive, and often more accurate than traditional animal testing or 2D cell cultures. However, creating a human version of the olfactory model presents unique challenges.
The primary hurdle lies in the collection of pure tissue. In mice, researchers can easily access the necessary stem cells. In humans, the process is far more invasive and technically difficult. Currently, obtaining olfactory tissue requires a patient to be anesthetized while a specialized brush—similar to a long COVID-19 testing swab—is inserted deep into the nasal cavity to harvest cells.
"It’s challenging to get pure olfactory tissue from humans," Lin notes. The procedure often results in a mixture of different cell types. Unlike the mouse model, where the researchers can precisely isolate the necessary components, human samples often contain a blend of respiratory stem cells and olfactory stem cells that are difficult to untangle.
The research team’s next challenge is to bridge this gap. They are working to develop a simple, cost-effective technique to separate human olfactory stem cells from their respiratory counterparts and "coax" them into growing into 3D organoids in the lab. If successful, this would allow doctors to take a small sample from a patient, grow their specific nasal tissue in a dish, and test which treatments or medications might best restore their sense of smell.
As the scientific community continues to grapple with the long-term effects of viral infections and the challenges of an aging population, the work at Tufts University offers a promising path forward. By revealing the hidden activity of "dormant" cells and providing the tools to study them, researchers are moving closer to a future where the loss of smell is no longer a permanent sentence, but a treatable condition.
