A team of researchers at Tufts University School of Medicine and the Graduate School of Biomedical Sciences (GSBS) has achieved a significant breakthrough in understanding how the human sense of smell is preserved. By developing a sophisticated, three-dimensional model to study the regeneration of nerve tissue within the nose, the researchers have uncovered evidence that a specific type of stem cell—previously dismissed as dormant—actually plays a critical, active role in maintaining olfactory function.
The findings, recently published in the journal Cell Reports Methods, offer a new lens through which scientists can view the complex cellular interactions that allow for the constant renewal of smell-sensing neurons. This discovery could have profound implications for treating conditions ranging from age-related sensory decline to the persistent loss of smell following viral infections like COVID-19.
The Regenerative Power of the Olfactory System
The human olfactory system is unique. Unlike the neurons in the central nervous system, which are notoriously difficult to repair or replace once damaged, the sensory neurons in the nasal cavity possess a remarkable, lifelong capacity for regeneration. Despite being subjected to the harsh, unpredictable elements of the outside environment—including airborne toxins, pathogens, and environmental pollutants—the nose is constantly replenishing its sensory cells.
However, this regenerative capacity is not infinite. Viral infections, chronic exposure to toxic substances, and the inevitable process of biological aging can all impair the function of these cells or hinder their ability to replicate. When these regenerative processes fail, the result is often a partial or complete loss of smell, known as anosmia. Understanding why this system declines is a primary goal for researchers investigating sensory loss, and the new 3D mouse model developed by the Tufts team provides a vital tool for observing these processes in real-time.
Unmasking the Role of Stem Cells
The research team focused their attention on two distinct types of stem cells found in the nasal cavity: horizontal basal cells (HBCs) and globose basal cells (GBCs). Traditionally, the scientific consensus held that GBCs were the primary engine of neuronal regeneration, while HBCs were largely considered "dormant" reserve cells, waiting in the wings to act only in the event of catastrophic tissue injury.
The new study challenges this binary view. Brian Lin, a research assistant professor in the Department of Developmental, Molecular and Chemical Biology and senior author on the study, explains that the two populations appear to be far more interdependent than previously understood.
"Our research suggests that these two stem cells may be interdependent," Lin says. "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 novel organoid model, the researchers identified a specific subpopulation of HBCs marked by the production of the protein KRT5. These cells were observed actively facilitating the generation of new olfactory neurons. When the team selectively depleted these KRT5-positive HBCs from their organoid cultures, the ability of the tissue to generate new neurons was significantly impaired. This observation confirms that these cells are not merely passive bystanders; they are essential, active participants in the regenerative process.
The Impact of Aging on Sensory Regeneration
Beyond identifying the roles of these stem cells, the team also sought to understand why the sense of smell often fades as humans age. By growing cells from mice of varying ages within their 3D model, the researchers observed a clear decline 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 insight into the age-related depletion of stem cells provides a promising target for future therapeutic interventions, potentially allowing scientists to develop strategies to "rejuvenate" the aging olfactory niche.
Developing an Accessible Research Tool
A major hurdle in biological research is the complexity and cost of creating experimental models. Recognizing this, the research team—led by former Ph.D. student Juliana Gutschow Gameiro, who visited GSBS from the State University of Londrina in Brazil—prioritized the creation of a model that was both effective and accessible.
"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 says. The goal was to build a tool that would allow researchers in labs with limited resources to study olfactory regeneration without needing highly specialized equipment or massive funding. By democratizing this research tool, the team hopes to accelerate the pace of discovery across the global scientific community.
Moving Toward Human Organoids
The ultimate ambition of the Tufts team is to translate their findings from mouse-tissue models to human organoids. Such a model would serve as a powerful platform for high-throughput drug screening, allowing scientists to test potential treatments for people suffering from chronic smell loss.
Organoids—miniature, simplified versions of organs grown in a lab—have already revolutionized research into the lungs, kidneys, and other major organs. They offer a significant advantage over animal models or traditional 2D cell cultures, as they more accurately mimic the structural and functional complexities of human tissue while being safer and more cost-effective than clinical trials.
However, the creation of human olfactory organoids remains a formidable challenge. Unlike the mouse models, which can be harvested under controlled laboratory conditions, obtaining pure olfactory tissue from human patients is difficult. The standard procedure involves inserting a brush into the nasal cavity, similar to a COVID-19 test. The problem, according to Lin, is that the collected sample contains a mixture of both respiratory stem cells and olfactory stem cells, which are notoriously difficult to separate.
The team’s current challenge is to engineer a simple, cost-effective technique to isolate these human olfactory stem cells and coax them into healthy growth within a laboratory setting. If successful, this would mark a major milestone in sensory research, potentially opening the door to personalized medicine and regenerative therapies for those who have lost their sense of smell. By bridging the gap between basic stem cell biology and clinical application, the researchers at Tufts are laying the groundwork for a future where the loss of one of our most vital senses is no longer a permanent condition.
