In a significant breakthrough for sensory biology, researchers at Tufts University School of Medicine and the Graduate School of Biomedical Sciences (GSBS) have developed a sophisticated three-dimensional model to study the regeneration of nerve tissue within the human nose. This innovation has led to a surprising discovery: a population of stem cells long dismissed as dormant may actually serve as a critical engine for maintaining the sense of smell.
The human olfactory system is a biological marvel. Unlike the central nervous system, where neurons are notoriously difficult to repair once damaged, the sensory neurons housed in the nasal cavity possess a remarkable, lifelong capacity for regeneration. This constant turnover allows the body to replace neurons exposed to the harsh, unpredictable elements of the outside world. However, this delicate process is not invincible. Viral infections—most notably COVID-19—as well as exposure to environmental toxins and the natural progression of aging, can impair the function of these cells or halt their replication entirely. When this happens, patients often suffer from hyposmia or anosmia, the partial or total loss of smell, conditions that can profoundly impact quality of life, nutrition, and mental health.
To better understand why this regenerative process falters, the Tufts research team, led by senior author Brian Lin, a research assistant professor in the Department of Developmental, Molecular and Chemical Biology, developed a new, highly accessible three-dimensional olfactory tissue mouse model, or organoid. By creating a simplified yet accurate representation of nasal tissue, the researchers aimed to observe how neurons are continually formed and to pinpoint the exact mechanisms that lead to decline during disease or the aging process. The findings of this study were recently published in the journal Cell Reports Methods.
Deciphering the Cellular Dialogue
The researchers utilized their new model to map the complex interaction between two specific types of stem cells found in the nose: horizontal basal cells (HBCs) and globose basal cells (GBCs). The study revealed that these two cell types do not operate in isolation; rather, they exist in a state of interdependence, communicating and supporting one another to facilitate the development of new smell-sensing nerve tissue.
"Our research suggests that these two stem cells may be interdependent," says 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."
This discovery challenges long-held assumptions in the field. Previously, HBCs were widely considered to be a reserve pool of cells that remained largely inactive unless triggered by severe injury. However, through the use of the new organoid model, the team identified a specific subpopulation of HBCs marked by the production of the protein KRT5. These cells appear to be active participants in the generation of new olfactory neurons, rather than mere bystanders.
To verify this, the team selectively depleted these KRT5-producing HBCs from the organoid cultures. The results were striking: the generation of new neurons was significantly impaired, confirming that these cells are essential players in the regenerative process. This suggests that the maintenance of our sense of smell relies on a much more active and nuanced cellular network than previously understood.
Aging and the Decline of Regeneration
Beyond understanding the mechanisms of healthy regeneration, the research team also sought to investigate why the sense of smell often fades as individuals grow older. By cultivating cells from mice of different ages within their 3D model, the researchers observed a clear, age-related decline in the ability to generate new neurons.
"We found a decline in the ability of the older mice cells to generate new neurons," Lin explains. "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."
If the depletion of GBCs is indeed the primary driver of age-related olfactory loss, this finding could eventually lead to targeted therapeutic interventions aimed at "rejuvenating" these stem cell populations, potentially restoring or slowing the decline of smell in older adults.
An Accessible Tool for Global Research
A primary priority for the research team, particularly for the study’s lead author, Juliana Gutschow Gameiro, was to ensure that the new model was practical and accessible. Gameiro, a former Ph.D. student visiting GSBS from the State University of Londrina in Brazil, focused on developing a method that could be easily replicated in laboratories with limited funding or specialized equipment.
The urgency of this work has been underscored by the global health crisis. "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 prioritizing a "user-friendly" design, the team hopes to democratize the study of olfactory regeneration. "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," he says. By lowering the barrier to entry, the researchers hope to accelerate discoveries across the international scientific community, fostering a more collaborative approach to treating smell-related disorders.
The Path Toward Human Organoids
The ultimate ambition of the Tufts team is to translate the success of their mouse-tissue model into a human organoid. Such a model would be an invaluable asset for drug screening, allowing researchers to test the efficacy of potential treatments for people suffering from chronic smell loss in a controlled, pre-clinical environment.
Organoids offer a distinct advantage over traditional research methods. They provide a more accurate representation of human tissue than simple cell cultures, while being significantly faster, less expensive, and more ethically straightforward than conducting initial tests on whole animals. While organoids have already been successfully developed for other organs, such as the lungs and kidneys, human olfactory tissue remains a challenging frontier.
"It’s challenging to get pure olfactory tissue from humans," Lin explains. The current clinical method for obtaining samples involves anesthetizing a patient and using a brush—similar to a COVID-19 test wand—to collect cells from deep within the nasal cavity. A significant technical hurdle is that these samples often contain a mixture of respiratory stem cells and olfactory stem cells, which are notoriously difficult to separate.
The research team’s next major challenge is to refine their methodology to create a simple, cost-effective technique for isolating human olfactory stem cells and successfully coaxing them to proliferate in a laboratory setting. If they succeed, it would mark a major milestone in regenerative medicine. By bridging the gap between basic stem cell biology and clinical application, the team at Tufts hopes to provide a pathway to therapeutic breakthroughs for the millions of people worldwide who live with the often-overlooked, yet life-altering, loss of their sense of smell.
