In a significant breakthrough for sensory science, researchers at Tufts University School of Medicine and the Graduate School of Biomedical Sciences (GSBS) have unveiled a new three-dimensional model that sheds light on the mysterious process of nerve regeneration in the nose. This innovative research, recently published in the journal Cell Reports Methods, suggests that a specific type of stem cell—long dismissed by the scientific community as largely dormant—may actually be a critical player in maintaining our sense of smell.
The human olfactory system is a marvel of biological resilience. Unlike the neurons found in the central nervous system, which are notoriously difficult to repair once damaged, the sensory neurons within the nasal cavity possess a remarkable, lifelong capacity for regeneration. This constant turnover allows the body to replace neurons exposed to the harsh, often toxic elements of the external environment. However, this delicate process is not infallible. Viral infections—most notably COVID-19—as well as chronic exposure to environmental toxins and the natural processes of aging, can impair this regenerative capacity. When these cells fail to replicate or function correctly, the result is a partial or total loss of smell, a condition that can profoundly impact a person’s quality of life and psychological well-being.
To better understand the mechanics behind this decline, 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 simplified, three-dimensional olfactory tissue model, or organoid. This "mini-organ" provides a controlled environment for scientists to observe how neurons are continually generated in the nose and, crucially, why that process falters over time.
Unlocking the Secrets of Nasal Stem Cells
At the heart of the research is the interplay between two distinct types of stem cells: horizontal basal cells (HBCs) and globose basal cells (GBCs). Traditionally, scientific consensus held that GBCs were the primary drivers of olfactory neuron production, while HBCs were viewed as a dormant "reserve" pool, waiting in the wings to be activated only in the event of extreme injury.
The Tufts study challenges this long-standing assumption. By utilizing their new organoid model, the team demonstrated that HBCs and GBCs exist in a state of complex 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," 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."
Through the use of the 3D model, the researchers identified a specific subpopulation of HBCs, characterized by their production of the protein KRT5. These cells appear to be active participants in the formation of new olfactory neurons. When the team selectively depleted these KRT5-producing HBCs from their organoid cultures, the generation of new neurons was significantly impaired. This finding serves as a compelling piece of evidence that these cells are not merely passive bystanders, but essential contributors to the regenerative landscape of the nasal epithelium.
The study also delved into the impact of age on these regenerative pathways. By growing cells from mice of varying ages within their 3D model, the researchers observed a clear decline in the ability of older cells to generate new neurons. "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."
A Tool for Global Research Accessibility
A notable aspect of this study is the deliberate design of the model itself. The lead author, Juliana Gutschow Gameiro, a former Ph.D. student visiting GSBS from the State University of Londrina in Brazil, focused her efforts on ensuring the model was both accessible and reproducible. In the context of modern biomedical research, where high-cost equipment and complex protocols can often create barriers to entry, the team prioritized creating a platform that is easy to produce in labs with limited funds and equipment.
The timing of this development is particularly pertinent. The surge of interest in olfactory health—driven in large part by the widespread reports of smell loss associated with COVID-19 and the ongoing study of neurodegenerative conditions like Parkinson’s disease—has created a demand for more robust research tools.
"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, the Tufts team hopes to catalyze a broader, more collaborative effort to solve the puzzle of olfactory dysfunction.
The Path Toward Human Organoid Therapy
The successful application of this mouse-tissue model is viewed by the researchers as a necessary stepping stone toward a more ambitious objective: the creation of a human olfactory organoid. Such a model would be an invaluable asset in the field of pharmacology, allowing researchers to screen drugs in a pre-clinical setting to identify potential treatments for those suffering from chronic smell loss.
Organoids offer a distinct advantage over traditional research methods. They are faster to develop, significantly less expensive than using whole animal models, and often provide a more accurate representation of human biology than standard cell cultures. While organoid technology has already made significant strides in replicating the function of lungs, kidneys, and other vital organs, human olfactory tissue has remained a difficult frontier.
The primary obstacle, as Dr. Lin explains, lies in the difficulty of obtaining pure samples. "It’s challenging to get pure olfactory tissue from humans," he notes. The current standard for sampling involves using a brush, similar to a COVID-19 test swab, to collect cells from deep within the nasal cavity. However, this process retrieves a mixture of both respiratory stem cells and olfactory stem cells, which are notoriously difficult to separate.
For the researchers at Tufts, the next chapter of their work is clear. They must now focus on developing a refined, inexpensive technique to isolate human olfactory stem cells from these mixed samples and successfully coax them to proliferate in a laboratory setting. Should they succeed, the development of a human organoid model would not only represent a triumph of tissue engineering but would also offer a glimmer of hope to millions worldwide who have lost their sense of smell, potentially paving the way for targeted, restorative therapies that were once thought to be impossible. As the team continues to bridge the gap between mouse models and human clinical applications, their work underscores the vital importance of understanding the hidden, regenerative potential of the cells within our own noses.
