Researchers at the Tufts University School of Medicine and the Graduate School of Biomedical Sciences (GSBS) have unlocked a significant mystery regarding the human sense of smell. By developing a sophisticated, three-dimensional model to observe the regeneration of nerve tissue within the nose, the team has discovered that a specific type of stem cell, long considered to be dormant, plays a far more active and essential role in preserving olfactory function than previously understood.
The findings, recently published in the journal Cell Reports Methods, offer a fresh perspective on the biological mechanisms that allow us to perceive scent. Unlike the central nervous system, which often struggles to repair itself after injury or degeneration, the sensory neurons in the nasal cavity possess a remarkable, lifelong capacity for regeneration. Despite being subjected to the constant, often harsh onslaught of the outside environment, these neurons are replaced in a continuous cycle of growth and renewal.
However, this regenerative process is not infallible. Viral infections—most notably the COVID-19 pandemic, which frequently left patients with lasting olfactory deficits—along with exposure to environmental toxins and the natural progression of aging, can significantly hinder the function of these cells. When this replication process falters, individuals may experience a partial or even complete loss of smell, a condition that can profoundly impact quality of life, nutrition, and safety.
To better understand why this biological repair system declines, the Tufts research team, led by senior author Brian Lin, a research assistant professor in the Department of Developmental, Molecular and Chemical Biology, devised a new, 3D olfactory tissue model. These organoids—miniature, simplified versions of organs grown in the laboratory—provide a controlled environment for scientists to observe how neurons are formed and why the process eventually hits a roadblock in disease or senescence.
Decoding the Interdependence of Stem Cells
At the heart of the study is the complex communication between two distinct types of stem cells located in the nose: horizontal basal cells (HBCs) and globose basal cells (GBCs). Traditionally, the scientific consensus viewed GBCs as the primary workhorses of olfactory regeneration, while HBCs were largely categorized as a dormant, reserve pool of cells that only activated in the event of severe, widespread injury.
The new organoid model challenges this assumption. By observing these cells in a 3D environment, the researchers demonstrated that HBCs and GBCs do not operate in isolation; rather, they appear to be highly interdependent.
"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."
Specifically, the team identified a subpopulation of HBCs, characterized by the production of the protein KRT5, that acts as a vital support system for the generation of new olfactory neurons. When the researchers selectively depleted these KRT5-expressing cells from the organoid cultures, the capacity of the tissue to generate new neurons was significantly impaired. This observation serves as strong evidence that these cells, once dismissed as mere placeholders, are essential, active players in the ongoing regenerative process.
The team also explored how this process changes over time. By cultivating cells taken from mice of varying ages, they observed a marked 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 study is required to confirm this mechanism, the researchers believe that understanding this decline is a critical first step toward developing future medical interventions designed to rejuvenate the aging olfactory system.
A Democratized Tool for Scientific Research
The development of this organoid model was driven not only by a need for biological insight but also by a desire for scientific accessibility. Lead author Juliana Gutschow Gameiro, a former Ph.D. student who visited the GSBS from the State University of Londrina in Brazil, was instrumental in ensuring the model was accessible to a broad range of labs.
Lin emphasized that the goal was to create a method that was easy to replicate, even for researchers working with limited funds or equipment. The urgency for such a tool has never been greater, given the rise in olfactory dysfunction linked to global health events and neurodegenerative conditions.
"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 studying olfactory epithelium, the researchers hope to accelerate discovery across the global scientific community. The organoid model provides a robust, cost-effective alternative to traditional animal testing or complex, high-maintenance human cell cultures, potentially streamlining the pipeline from basic research to therapeutic application.
Looking Toward Human Applications
While the current model utilizes mouse tissue, the ultimate ambition of the research team is to translate these findings into a human organoid. Such a model would represent a significant milestone in pre-clinical research, providing a platform to screen pharmaceutical drugs that could potentially restore or protect the sense of smell in patients suffering from permanent or progressive anosmia.
The transition from mouse to human, however, presents unique challenges. Creating human organoids requires the isolation of pure olfactory stem cells, which is notoriously difficult. In clinical settings, nasal tissue is typically collected via a brush—a procedure similar to the nasal swabs used for COVID-19 testing. However, the resulting sample often contains a mixture of both respiratory and olfactory stem cells, which are incredibly difficult to separate from one another once collected.
Developing a reliable, inexpensive, and efficient technique to isolate these human olfactory stem cells and coax them into growth remains the team’s primary technical hurdle. Should they succeed, it would open the door to highly personalized research, allowing scientists to test how different individuals’ cells respond to various treatments in a controlled laboratory environment.
As the scientific community continues to grapple with the long-term impacts of pandemic-related health issues and the aging population’s susceptibility to sensory decline, the work at Tufts offers a promising pathway forward. By uncovering the hidden roles of previously ignored stem cells and providing researchers with the tools to study them, this study lays the groundwork for future therapies that could one day restore the sense of smell to thousands of people worldwide. The team’s focus remains clear: moving from the laboratory dish to a functional, reliable, and accessible human model that can change the way we approach olfactory health.
