In the ongoing quest to understand why some individuals suffer from the persistent loss of smell—a condition brought into sharp focus by the COVID-19 pandemic—researchers at Tufts University School of Medicine and the Graduate School of Biomedical Sciences (GSBS) have unveiled a breakthrough in how we study the nose’s remarkable ability to repair itself. By engineering a novel, three-dimensional model of olfactory tissue, the research team has discovered that a specific population of stem cells, long assumed to be dormant, actually serves as a vital engine for preserving our sense of smell.
The findings, recently published in the journal Cell Reports Methods, offer a new perspective on the cellular mechanics of the nasal cavity. Unlike the central nervous system, where nerve regeneration is notoriously limited, the sensory neurons responsible for our sense of smell possess a unique, lifelong capacity to regenerate. This continuous turnover is essential because the nasal lining is constantly exposed to the outside environment, including potential toxins, viruses, and pollutants that can damage sensitive tissues.
However, this regenerative capacity is not invincible. Factors such as viral infections, environmental exposure, and the inevitable process of biological aging can disrupt this cycle. When the ability of these neurons to replicate falters, the result is often a diminished sense of smell—anosmia or hyposmia—which can profoundly impact a person’s quality of life, nutritional intake, and safety.
Understanding the Cellular "Architects" of the Nose
At the heart of this regenerative process are two primary types of stem cells: horizontal basal cells (HBCs) and globose basal cells (GBCs). For years, the scientific community focused heavily on GBCs as the primary drivers of neuron production. HBCs, by contrast, were largely sidelined in research narratives, frequently characterized as a dormant reserve pool activated only under extreme conditions of severe tissue injury.
The Tufts research team’s new organoid model—a miniature, simplified version of olfactory tissue grown in a lab—challenges this long-standing assumption. Through rigorous observation of how these two cell types interact within the 3D environment, the researchers identified a specific subpopulation of HBCs, identified by their expression of the protein KRT5.
"Our research suggests that these two stem cells may be interdependent," explains Brian Lin, senior author on 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 selectively depleting these KRT5-producing HBCs from the organoid cultures, the team observed a significant impairment in the generation of new olfactory neurons. This finding effectively reclassifies these cells from passive bystanders to essential participants in the ongoing maintenance of the olfactory system. The interdependence between HBCs and GBCs suggests a more complex, nuanced communication network within the nose than previously imagined.
The Impact of Aging on Regeneration
Beyond the discovery of the HBCs’ role, the study also sheds light on why the sense of smell often fades as we age. By culturing cells taken from mice at different stages of life, the team was able to observe the aging process in real-time within their 3D models.
"We also looked at cells from mice of different ages and grew them in the model," Lin notes. "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."
This age-related decline remains a major hurdle in regenerative medicine. If the GBC population is indeed depleting, or if the communication between HBCs and GBCs becomes inefficient with time, the team’s findings provide a clear target for future therapeutic interventions aimed at reversing or slowing that loss of function.
Democratizing Olfactory Research
A significant achievement of this study is not just the biological discovery, but the development of the tool itself. Lead author Juliana Gutschow Gameiro, a former Ph.D. student visiting GSBS from the State University of Londrina in Brazil, focused her efforts on ensuring the model was accessible. In scientific research, the complexity and cost of equipment often act as barriers to entry for smaller labs. Gameiro’s goal was to create a robust model that could be replicated with limited resources.
"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."
By lowering the technical threshold for studying these cells, the team hopes to catalyze a broader, more collaborative effort to solve the mysteries of olfactory health. The organoid model allows for the rapid testing of variables in a controlled environment, moving research away from the ethical and logistical complexities of whole-animal studies where possible.
The Road Toward Human Organoids
While the current mouse-tissue model represents a major step forward, the ultimate goal of the Tufts team is to translate these findings into a human-derived organoid. Such a model would be a game-changer for pharmaceutical research, enabling scientists to screen drugs for the treatment of olfactory loss in a way that is faster, more cost-effective, and more predictive of human response than existing methods.
Organoids have already transformed the study of other organs, including the lungs and kidneys, by providing a "human-like" substrate for testing. However, creating an olfactory organoid from human cells presents a unique set of challenges.
"It’s challenging to get pure olfactory tissue from humans," Lin explains. To collect the necessary cells, medical professionals must use a specialized brush, similar to those used in COVID-19 nasal testing, to reach deep into the nasal cavity. The difficulty lies in the fact that the sample contains a mixture of both respiratory and olfactory stem cells. Currently, these two populations are notoriously difficult to separate, which complicates the development of a pure olfactory organoid culture.
As the team looks to the future, their focus is squarely on perfecting a technique that can reliably isolate these human olfactory stem cells. Once they can successfully coax these cells to grow and thrive in a laboratory setting, it will open the door to a new era of personalized medicine for those suffering from the loss of smell.
The work of the Tufts researchers serves as a reminder that even the most "dormant" components of our biology may hold the keys to restoring our senses. By bridging the gap between basic stem cell biology and accessible laboratory techniques, the team is moving closer to a future where the loss of smell is no longer an inevitable or untreatable consequence of aging or disease. The path forward involves continuing to refine their understanding of the delicate dance between HBCs and GBCs, and eventually, turning that knowledge into treatments that can help individuals reclaim a vital, often overlooked, part of their human experience.
