A team of researchers at Tufts University School of Medicine and the Graduate School of Biomedical Sciences (GSBS) has unveiled new insights into how the human nose maintains its sense of smell, potentially opening doors to treatments for millions suffering from olfactory loss. By utilizing a newly devised, three-dimensional model to study the regeneration of nerve tissue, the scientists discovered that a specific type of stem cell, previously thought to be largely dormant, plays a far more critical role in preserving olfactory function than once believed.
Unlike the central nervous system, where damage is often permanent, the sensory neurons within the nasal cavity possess a remarkable, lifelong capacity for regeneration. This constant turnover allows humans to maintain their sense of smell despite the nose’s ongoing exposure to environmental toxins, pollutants, and pathogens. However, this delicate biological process is vulnerable. Viral infections—most notably those linked to COVID-19—as well as toxic exposure and the natural processes of aging, can severely impair the function or reproductive capacity of these cells. When the regeneration process falters, the result can be a partial or total loss of smell, a condition that profoundly impacts quality of life, nutrition, and safety.
To better understand the mechanisms governing this regeneration and why they decline over time, the research team developed an accessible, three-dimensional olfactory tissue mouse model, known as an organoid. Their findings, which were recently published in the journal Cell Reports Methods, illuminate the complex relationship between two primary types of stem cells found in the nasal cavity: horizontal basal cells (HBCs) and globose basal cells (GBCs).
Unlocking the Communication Between Stem Cells
The study reveals that the regeneration of smell-sensing nerve tissue is not a solitary act but a collaborative effort between these two cell populations. According to the research, HBCs and GBCs communicate and support one another to ensure the nose continues to produce new neurons.
"Our research suggests that these two stem cells may be interdependent," explains Brian Lin, a research assistant professor in the Department of Developmental, Molecular and Chemical Biology and the senior author of the study. "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 the newly created organoid model, the team successfully identified a specific subpopulation of HBCs, distinguished by their production of the protein KRT5. These cells were found to be active participants in the generation of new olfactory neurons. Through a series of experiments, the researchers observed that these particular HBCs were essential to the formation of the organoids. When these KRT5-positive cells were selectively depleted from the cultures, the generation of new neurons was significantly impaired, confirming that these once-overlooked stem cells are vital architects of the regenerative process.
The study also investigated the impact of age on this biological machinery. By growing cells from mice of different ages within the organoid model, the team observed a clear decline in the ability of older cells to generate new neurons. Lin and his colleagues hypothesize that this decline is linked to a reduction in the GBC population as the organism ages. While further research is required to definitively confirm this hypothesis, the finding provides a roadmap for future investigations into potential therapeutic interventions aimed at "rejuvenating" these cells to restore olfactory function in aging populations.
Developing an Accessible Research Tool
A primary motivation behind the development of this new model was the need for simplicity and cost-effectiveness. Lead author Juliana Gutschow Gameiro, a former visiting Ph.D. student at GSBS who came to Tufts from the State University of Londrina in Brazil, focused her efforts on ensuring the model could be replicated in laboratories with limited budgets or specialized equipment.
The urgency for such a tool has grown significantly in recent years. "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 notes.
By providing a platform that is easy to use, the team hopes to empower scientists who may not be specialized stem cell biologists to conduct meaningful research. "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 Path Toward Human Organoids and Drug Screening
The ultimate objective of this research is to translate the success of the mouse-tissue model into a human-derived organoid. Such a model would serve as a powerful tool for high-throughput drug screening, allowing researchers to test various pharmaceutical compounds to identify those capable of treating individuals who have suffered significant or total loss of smell.
Organoids—miniature, simplified versions of organs grown in a lab setting—have revolutionized pre-clinical research. They provide a more efficient, less expensive, and ethically advantageous alternative to traditional animal testing or limited human cell cultures. While organoid models have already been established for human organs such as the lungs and kidneys, a reliable model for human olfactory tissue has remained elusive.
The hurdle to creating a human-equivalent model lies in the complexity of sample collection. "It’s challenging to get pure olfactory tissue from humans," Lin explains. The standard collection process involves anesthetizing a patient and using a brush—similar to those used in COVID-19 testing—to sample the deep reaches of the nasal cavity. However, unlike the mouse model, the human samples collected via this method contain a mixture of both respiratory stem cells and olfactory stem cells, which are notoriously difficult to isolate from one another.
Currently, the Tufts team is focused on overcoming this technical barrier. Their next challenge is to refine a simple, inexpensive technique to effectively separate human olfactory stem cells and cultivate them in the laboratory environment. If successful, this advancement could bridge the gap between basic biological discovery and clinical application, providing a long-awaited lifeline for those struggling with the loss of their sense of smell. By demystifying the regenerative potential of the nose, the researchers are laying the groundwork for a new era of sensory medicine, transforming our understanding of how the body repairs its most delicate and vital nerve tissues.
