In a discovery that challenges long-held assumptions about how the human body maintains its sense of smell, researchers at Tufts University School of Medicine and the Graduate School of Biomedical Sciences (GSBS) have identified a specific type of stem cell as a primary driver of nasal tissue regeneration. Using a sophisticated, newly devised three-dimensional model to observe the intricate biological processes of the olfactory system, the team found that a population of stem cells previously thought to be largely dormant actually plays a vital role in preserving and repairing the nerve tissue responsible for detecting odors.
The study, published in the journal Cell Reports Methods, provides a new lens through which scientists can view the regenerative capabilities of the nose. While the central nervous system is notoriously limited in its ability to repair itself after injury or disease, the sensory neurons located within the nasal cavity possess a remarkable, lifelong capacity for renewal. These neurons are constantly exposed to the external environment, facing a barrage of toxins, pollutants, and pathogens. To survive this constant exposure, the body relies on a complex internal system of stem cells to replace damaged or aging neurons.
However, when this regenerative process is interrupted—whether by viral infections like COVID-19, prolonged exposure to environmental toxins, or the natural process of aging—the result can be a significant decline in olfactory function. This can lead to hyposmia, a reduced ability to smell, or anosmia, the total loss of the sense. By developing a more accurate 3D model of this tissue, the Tufts researchers have opened a new door toward understanding why these regenerative mechanisms fail and how they might be restored.
The Interdependence of Nasal Stem Cells
At the heart of the study is the relationship between two specific types of stem cells found in the olfactory epithelium: horizontal basal cells (HBCs) and globose basal cells (GBCs). Historically, the scientific community viewed these two cell types through a relatively narrow lens. GBCs were seen as the primary "workhorses" of the nose, constantly dividing and differentiating into new sensory neurons to replace those that died off. In contrast, HBCs were largely characterized as a reserve population—dormant cells that only activated in response to severe, catastrophic injury to the nasal lining.
The new research from Tufts suggests that this division of labor is far more nuanced than previously understood. Through the use of their 3D mouse-tissue model, also known as an organoid, the team observed a high degree of communication and support between the two cell populations.
"Our research suggests that these two stem cells may be interdependent," explained Brian Lin, the study’s senior author 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 monitoring the organoids as they developed, the researchers identified a specific subpopulation of HBCs characterized by the production of a protein called KRT5. Rather than sitting idly by, these KRT5-positive cells were found to be active participants in the formation of new olfactory tissue. The team discovered that these cells provide a necessary foundation or signaling environment that allows the GBCs to function effectively.
To test the importance of these "dormant" cells, the researchers conducted an experiment where the KRT5-producing HBCs were selectively depleted from the organoid cultures. The results were stark: without the support of these specific HBCs, the generation of new sensory neurons was significantly impaired. This finding suggests that HBCs are not just a "break glass in case of emergency" backup system, but are essential players in the day-to-day regenerative cycle of the nose.
Understanding Aging and the Decline of Smell
Beyond identifying the roles of specific cell types, the Tufts team used their 3D model to investigate one of the most common causes of olfactory loss: aging. As humans age, the sense of smell often dulls, a condition that can impact nutrition, safety, and overall quality of life. Until now, the exact cellular mechanics behind this decline remained somewhat elusive.
The researchers compared cells harvested from mice of different ages and grew them within their organoid model to observe how age impacted the regenerative process. They found a clear and measurable decline in the ability of cells from older mice to generate new neurons.
"We found a decline in the ability of the older mice cells to generate new neurons," Lin said. "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 study suggests that as the population of GBCs dwindles or becomes less efficient with age, the entire regenerative cycle slows down. If the HBCs and GBCs are indeed interdependent, the failure of one group inevitably hampers the other, leading to a permanent reduction in the number of active sensory neurons. This insight is particularly valuable for researchers looking to develop therapies that could potentially "restart" or "rejuvenate" the stem cell environment in the elderly, helping them regain a sense of smell that has faded over decades.
An Easy-To-Use Model
One of the most significant contributions of this study is the model itself. The lead author of the study, Juliana Gutschow Gameiro, joined the Tufts team as a visiting Ph.D. student from the State University of Londrina in Brazil. Her primary goal was to create a 3D organoid model that was not only biologically accurate but also accessible to the wider scientific community.
In the world of high-level biological research, specialized equipment and expensive reagents can often limit the ability of smaller labs to contribute to major breakthroughs. Gameiro and Lin sought to democratize the study of olfactory tissue by designing a model that was easy to create, even in labs with limited funds.
The timing of this development is critical. Since the onset of the global COVID-19 pandemic, interest in the olfactory system has surged. The virus’s well-documented ability to cause sudden and sometimes permanent loss of smell has brought a new level of urgency to the field. Furthermore, smell loss is increasingly recognized as an early warning sign for neurodegenerative conditions, such as Parkinson’s disease and Alzheimer’s.
"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 noted.
By providing a simplified, reproducible model, the Tufts team hopes to enable researchers who are not necessarily stem cell specialists to study the nasal cavity. Whether a scientist is investigating the impact of a specific virus or testing the toxicity of an industrial chemical, the 3D organoid offers a platform to observe how those factors affect the delicate balance of HBCs and GBCs without the need for complex animal surgeries or prohibitively expensive technology.
Next Step: A Human Organoid
While the mouse-based organoid has already yielded significant insights, the researchers are already looking toward the next major milestone: the creation of a human olfactory organoid. The transition from animal models to human tissue is a critical step in the development of medical treatments, as it allows for more accurate drug screening and a better understanding of human-specific disease pathways.
The use of organoids in pre-clinical research offers several advantages over traditional methods. They are faster and less expensive to maintain than whole animal colonies, and they provide a more realistic three-dimensional environment than flat, two-dimensional cell cultures. Organoids have already been successfully developed for other major organs, including the lungs and kidneys, but the human olfactory system has proven to be a unique challenge.
The primary hurdle lies in the collection of pure tissue. "It’s challenging to get pure olfactory tissue from humans," Lin explained. To collect these cells, patients must be anesthetized while a specialized brush—similar to the swabs used for COVID-19 testing, but designed to reach much deeper into the nasal vault—is used to harvest tissue.
The difficulty arises once the cells are out of the body. In humans, the stem cells for the respiratory system and the stem cells for the olfactory system are physically intermingled. In the current collection process, it is extremely difficult to separate the two. For an organoid to be effective, it must be composed of the correct cell types; a "human olfactory organoid" contaminated with too many respiratory cells would not accurately reflect how the sense of smell functions or fails.
The research team’s next challenge is to develop a simple, inexpensive technique for separating out these human olfactory stem cells and coaxing them to grow in a laboratory setting. If successful, this would pave the way for a human model that could be used to screen potential drugs designed to treat anosmia. Such a tool would be a game-changer for the millions of people worldwide living with a diminished sense of smell, providing a platform to test therapies that could one day restore a sense that is fundamental to the human experience.
