In the intricate architecture of the human sensory system, the ability to perceive odors is often taken for granted—until it vanishes. For millions of people affected by viral infections, environmental toxins, or the natural progression of aging, the loss of smell is a profound disruption to quality of life. However, a groundbreaking study from researchers at the Tufts University School of Medicine and the Graduate School of Biomedical Sciences (GSBS) has illuminated a new path toward understanding how the nose repairs itself, revealing that a class of stem cells previously dismissed as largely inactive may actually be the unsung heroes of nasal regeneration.
The study, recently published in the journal Cell Reports Methods, utilizes a sophisticated, three-dimensional mouse-tissue model—an organoid—to map the complex cellular conversations that govern the birth of new sensory neurons. By peering into this micro-environment, the research team discovered that horizontal basal cells (HBCs), which were long thought to remain dormant unless triggered by catastrophic injury, play a continuous and essential role in supporting the production of smell-sensing nerve tissue.
The Resilient Frontier of the Nasal Cavity
Unlike the delicate neurons of the central nervous system, which are notoriously poor at self-repair following damage, the sensory neurons located in the nasal cavity possess a remarkable, lifelong capacity for regeneration. This biological resilience is a necessity; these neurons are among the few parts of the nervous system directly exposed to the harsh outside environment. Every breath brings a barrage of potential threats, from fluctuating temperatures and humidity to airborne pathogens and chemical pollutants.
Despite this inherent toughness, the regenerative machinery of the nose is not invincible. Factors such as the inflammatory response triggered by COVID-19, chronic exposure to industrial toxins, or the gradual cellular senescence associated with aging can stifle the ability of these cells to replicate. When this process falters, the result is hyposmia (a diminished sense of smell) or anosmia (the total loss of smell). To investigate why this process fails and how it might be jump-started, the Tufts team needed a way to observe the cellular interactions in real-time, leading to the creation of their new olfactory organoid.
Unveiling the Interdependence of Stem Cells
At the heart of the study is the relationship between two primary types of stem cells found in the olfactory epithelium: horizontal basal cells (HBCs) and globose basal cells (GBCs). Historically, the scientific consensus held a somewhat binary view of these cells. GBCs were seen as the primary "workhorses," constantly dividing to replace neurons under normal conditions. In contrast, HBCs were viewed as a reserve population—a "break glass in case of emergency" backup that only became active when the tissue suffered severe trauma.
The Tufts research, however, challenges this traditional hierarchy. Using their 3D model, the team identified a specific subpopulation of HBCs, characterized by the production of a protein called KRT5. Rather than sitting idly by, these cells were found to be active participants in the daily maintenance of the olfactory system.
"Our research suggests that these two stem cells may be interdependent," explains Brian Lin, senior author on the study and a research assistant professor in the Department of Developmental, Molecular and Chemical Biology at Tufts. "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 interdependence suggests a much more collaborative ecosystem than previously imagined. When the researchers experimentally depleted these KRT5-producing HBCs from their organoid cultures, the results were striking: the generation of new neurons was significantly impaired. This finding suggests that GBCs cannot operate at peak efficiency without the metabolic or signaling support provided by their HBC counterparts. The "dormant" cells are, in fact, essential scaffolds for the regenerative process.
An Easy-To-Use Model for Global Research
The development of the organoid itself represents a significant leap forward in bioengineering, particularly in its accessibility. The lead author of the study, Juliana Gutschow Gameiro, joined the Tufts team as a visiting Ph.D. student from the State University of Londrina in Brazil. Her mission was to create a model that was not only biologically accurate but also practical for labs that may lack the massive budgets or specialized equipment of elite Western institutions.
The resulting mouse-tissue organoid is designed to be "easy-to-create," a feature that Brian Lin emphasizes is critical for the current scientific climate. The global pandemic brought the issue of olfactory dysfunction into the mainstream, as millions of COVID-19 patients reported a sudden loss of taste and smell. This has sparked a surge of interest from researchers who may not be experts in stem cell biology but are eager to find clinical solutions.
"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 democratizing access to this type of 3D modeling, the Tufts team hopes to accelerate the pace of discovery across the globe, allowing more scientists to test how different chemicals, viruses, or genetic factors influence the health of nasal neurons.
The Impact of Aging and the Quest for Rejuvenation
One of the most pressing questions in olfactory research is why our sense of smell fades as we grow older. It is a common clinical observation that elderly individuals often lose the ability to detect subtle scents, which can lead to decreased appetite, poor nutrition, and an inability to detect hazards like leaking gas or spoiled food.
The Tufts researchers used their model to investigate this decline by growing organoids from the cells of mice of various ages. Their observations confirmed a clear downward trend: cells harvested from older mice were significantly less capable of generating new neurons than those from younger mice.
"We found a decline in the ability of the older mice cells to generate new neurons," Lin notes. The team believes this failure is tied to a dwindling population of GBCs as the animal ages. However, the discovery of the HBCs’ supportive role adds a new layer to this mystery. If HBCs are required to support GBCs, is the aging of the "dormant" cells the real bottleneck?
"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," Lin says. The organoid model provides the perfect "test kitchen" for these rejuvenation experiments, allowing researchers to introduce different growth factors or drugs to see if the youthful regenerative capacity of the tissue can be restored.
Next Step: A Human Organoid
While the mouse model has provided invaluable insights into the basic biology of the nose, the ultimate prize is the development of a human olfactory organoid. Such a tool would revolutionize the way we treat anosmia and other sensory disorders.
In the current pharmaceutical pipeline, drug testing often relies on animal models or two-dimensional human cell cultures, neither of which perfectly replicates the complex, 3D environment of the human body. Organoids—already successfully developed for the lungs, kidneys, and brain—bridge this gap, offering a more accurate platform for pre-clinical trials. They are faster, less expensive, and potentially more predictive of human responses than whole-animal testing.
However, creating a human version of the olfactory organoid presents unique logistical hurdles. Unlike mice, from whom tissue can be harvested relatively easily in a controlled environment, obtaining pure olfactory tissue from human subjects is a delicate and invasive procedure.
"It’s challenging to get pure olfactory tissue from humans," Lin explains. To collect the necessary cells, individuals must be anesthetized while a specialized brush—resembling a long-handled COVID-19 test swab—is inserted deep into the nasal vault to reach the olfactory epithelium. The primary difficulty arises after the collection: the sample is often a mixture of respiratory stem cells (which line the majority of the nose) and the specific olfactory stem cells needed for the organoid.
Unlike the mouse model, where these cell types are more easily distinguished, human respiratory and olfactory stem cells collected via brushing are difficult to separate. The Tufts team is now focusing their efforts on developing a simple, cost-effective technique to isolate these human olfactory stem cells and "coax" them into growing into functional 3D tissue in the lab.
If successful, this human organoid would serve as a high-throughput screening tool. Researchers could take a patient’s own cells, grow an organoid, and then test an array of medications to see which ones effectively stimulate neuron growth for that specific individual. This move toward personalized medicine could offer hope to those suffering from long-term smell loss, whether caused by the lingering effects of a virus, the toxic side effects of chemotherapy, or the inevitable march of time.
By uncovering the secret life of "dormant" stem cells and providing a new tool for the global scientific community, the researchers at Tufts are not just mapping the nose—they are laying the groundwork for a future where the loss of a sense is no longer a permanent sentence.
