Stem Cells and Cell-Free Therapies for Olfactory Epithelium Regeneration: Insights from Experimental Models

Olfactory impairment is one of the most common diseases of the sense organs, and it is closely related to quality life. Although the molecular mechanism of olfaction was recently brought to light, the pathophysiology and effective treatments for olfactory dysfunction still remain challenging. Olfactory impairment can be caused by the degeneration of olfactory receptor neurons in the nose and also by the degeneration of the olfactory bulb of the olfactory cortex. Several studies have shown that stem cells promote the regeneration of the olfactory neuroepithelium after permanent damage in anosmic mice. Transplanted adipose stem cells differentiated into olfactory receptor neurons and endothelial cells. Recently, cell-free approaches using stem cell-derived secretome and extracellular vesicles (EVs) have emerged as a safer, more controllable alternative. These vesicles contain biologically active cargo such as neurotrophins, cytokines, and microRNAs that promote neurogenesis and modulate inflammation. Although direct application in anosmia models remains limited, findings from related neural injury models suggest that secretome- and EV-based therapies may achieve comparable regenerative efficacy to stem cell transplantation. This review summarizes current evidence on the regenerative capacity of stem cells and their secretome or EVs as therapeutic strategies for olfactory epithelium regeneration.