In a significant stride toward understanding how the human body repairs its sensory systems, researchers at Tufts University School of Medicine and the Graduate School of Biomedical Sciences (GSBS) have unveiled a groundbreaking three-dimensional model for studying the regeneration of nerve tissue in the nose. This innovative approach has led to the discovery that a specific type of stem cell, long dismissed by the scientific community as dormant, plays a far more critical role in preserving our sense of smell than previously imagined.
The findings, recently published in the journal Cell Reports Methods, offer a fresh perspective on the biological mechanisms that allow our olfactory system to endure the constant, often harsh, exposure of the outside environment. Unlike the delicate neurons of the central nervous system, which have limited capacity for self-repair, the sensory neurons within the nasal cavity possess a remarkable, lifelong ability to regenerate. This continuous renewal process is essential for maintaining our olfactory function, yet it is a process that remains vulnerable to disruption.
The Fragility of Olfaction
The sense of smell is more than a simple sensory experience; it is a vital component of human health, nutrition, and safety. However, this system is susceptible to damage from various external and internal factors. Viral infections—most notably the global COVID-19 pandemic—can cause temporary or, in some cases, permanent loss of smell. Furthermore, chronic exposure to environmental toxins and the natural progression of biological aging can diminish the function of olfactory neurons or hamper their ability to replicate, leading to partial or complete anosmia, the medical term for the loss of smell.
To better understand why this regenerative process falters, the research team, led by senior author Brian Lin, a research assistant professor in the Department of Developmental, Molecular and Chemical Biology at Tufts, developed a new, three-dimensional olfactory tissue mouse model. Known as an organoid, this model provides a controlled, simplified environment that allows scientists to observe how neurons are continually formed within the nose and, crucially, to pinpoint where this process breaks down during disease or the aging process.
Revealing the Interdependence of Stem Cells
The study centers on the complex interactions between two primary types of stem cells found within the nasal tissue: horizontal basal cells (HBCs) and globose basal cells (GBCs). Traditionally, scientific consensus held that GBCs were the primary engine of neuronal regeneration, while HBCs were viewed as a reserve pool—largely dormant cells that only activated in the event of catastrophic injury to the tissue.
"Our research suggests that these two stem cells may be interdependent," explains Dr. 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 utilizing their newly developed organoid model, the team identified a specific subpopulation of HBCs marked by the expression of the protein KRT5. These cells, they discovered, are far from inactive. Instead, they act as active facilitators in the generation of new olfactory neurons. The researchers demonstrated that when these KRT5-producing HBCs were selectively depleted from the organoid cultures, the formation of new neurons was significantly impaired. This observation serves as a powerful indicator that these cells are essential, active players in the ongoing regenerative process rather than mere bystanders waiting for a crisis.
The Impact of Aging on Regeneration
In addition to exploring the mechanisms of cellular communication, the team sought to understand the biological decline of smell associated with getting older. By growing cells from mice of varying ages in their 3D organoid model, the researchers observed a marked decrease in the regenerative capacity of cells derived from older subjects.
"We found a decline in the ability of the older mice cells to generate new neurons," Lin notes. "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 line of inquiry represents a promising frontier for regenerative medicine: if the decline in smell is indeed linked to a specific reduction in the GBC population, it may eventually be possible to develop therapeutic interventions to "rejuvenate" these cells, potentially restoring or preserving olfactory function in older populations.
A Democratized Approach to Research
A key objective for the team was ensuring that their methodology was accessible to the broader scientific community. Juliana Gutschow Gameiro, the lead author of the study and a former visiting Ph.D. student at GSBS, played a pivotal role in this effort. Coming to Tufts from the State University of Londrina in Brazil, Gameiro was dedicated to crafting a model that could be replicated in laboratories with limited funding or specialized equipment.
The urgency of this work has been amplified by the public health challenges of the last few 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," 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 barrier to entry for this type of research, the team hopes to accelerate the pace of discovery, allowing labs around the world to contribute to the understanding of olfactory health without the need for prohibitively expensive or complex infrastructure.
Toward a Human Organoid
The ultimate goal of the Tufts team is to translate the success of their mouse-tissue model into a human organoid. Such a model would serve as a transformative tool for pre-clinical drug screening, enabling researchers to test potential treatments for people suffering from diminished or absent senses of smell without the ethical and logistical complexities of using whole animals or current human cell culture methods.
Organoids have already proven their value in studying other systems, including the lungs and kidneys, but human olfactory tissue remains a difficult target. "It’s challenging to get pure olfactory tissue from humans," Lin explains. The collection process involves anesthetizing a patient and using a brush—similar to a COVID-19 test swab—to reach deep into the nasal cavity. However, unlike in the mouse model, the human samples collected via this method contain a mixture of respiratory stem cells and olfactory stem cells, which are notoriously difficult to separate.
The research team is now focused on solving this technical hurdle. Their next challenge is to develop a simple, cost-effective technique to isolate human olfactory stem cells and coax them to grow in a laboratory setting. If successful, this would represent a major milestone in the field, moving science one step closer to clinical solutions for millions of people worldwide who live with the often-isolating reality of losing their sense of smell. For now, the team’s findings regarding HBCs and the efficacy of their 3D mouse model stand as a vital building block in the quest to map the regenerative capacity of the human nose.
