Dawn of a new era in olfactory regeneration: Pediatric stem cell therapy enters the era of long-term validation

Abstract

A recently published prospective study marks a breakthrough for congenital olfactory disorders in children. The study provides the first long-term, three-year follow-up data, robustly demonstrating the durable efficacy and safety of autologous nasal epithelial stem cell transplantation. This work reveals immense therapeutic potential for a condition traditionally considered untreatable. However, this milestone achievement also presents new challenges. To translate this pioneering therapy from a single-center success to a global standard, multicenter, controlled clinical trials must be initiated immediately. Only through rigorous validation can we ensure its widespread adoption and ultimately bring hope to millions of children worldwide.

Key Words: Congenital olfactory disorders; Nasal epithelial stem cells; Pediatric anosmia; Stem cell therapy; Clinical translation; Regenerative medicine

Core Tip: This letter highlights a landmark prospective study that provides the first three-year follow-up evidence of autologous nasal epithelial stem cell transplantation in children with congenital olfactory disorders. The findings confirm durable efficacy and safety, transforming what was once deemed untreatable into a feasible therapeutic pathway. However, to establish this pioneering approach as a global standard, multicenter, controlled clinical trials are urgently required to validate and extend these promising results.

TO THE EDITOR

Olfactory dysfunction is increasingly recognized as a significant public health issue, with more than 20% of the adult population affected when partial loss is included[1]. Beyond its sensory role, impaired olfaction compromises nutrition and safety awareness and contributes to psychosocial consequences, including depression and diminished quality of life[2]. While most cases are acquired, typically resulting from upper respiratory infections, sinonasal disease, trauma, or aging, congenital olfactory disorders (CODs) represent a rare but particularly impactful subset. Epidemiological estimates suggest that approximately 1 in 10000 individuals are born with congenital anosmia, encompassing both syndromic and non-syndromic forms[3]. Despite their low prevalence, CODs impose disproportionate burdens by affecting appetite regulation, developmental milestones, and emotional well-being, while no approved or standardized therapeutic interventions currently exist, leaving affected children and families without viable treatment options[4,5].

Preclinical research on olfactory regeneration has relied on several inducible hyposmia models, such as zinc sulfate (ZnSO₄) intranasal instillation[6] and methimazole systemic administration[7], both of which selectively ablate olfactory receptor neurons and basal stem cells in rodents. Using these models, different cell types - including olfactory ensheathing cells[8], neural stem/progenitor cells[9,10], and mesenchymal stem cells (MSCs)[11] - have shown varying degrees of olfactory epithelial regeneration and behavioral recovery. Among them, autologous nasal epithelial stem cells (NESCs) provide lineage compatibility and low immunogenicity, addressing key translational challenges such as donor-site morbidity and immune rejection[12]. Despite the minimally invasive harvesting process, these characteristics justify their selection for pediatric clinical application[13].

Against this backdrop, the recent prospective clinical study by Ni et al[14] constitutes a genuine milestone. Enrolling fifty pediatric patients with CODs, the investigators performed autologous NESC transplantation and conducted three-year longitudinal follow-up. Their findings demonstrate not only robust improvement in validated olfactory function tests (Sniffin’ Sticks and UPSIT-Children’s Version), but also significant enhancement in quality of life indices. Safety outcomes were particularly reassuring: No serious adverse events were observed, and only minor, self-limiting complications occurred in a small fraction of patients. Importantly, endoscopic and electro-olfactogram assessments corroborated functional recovery with morphological and electrophysiological evidence of olfactory epithelium regeneration. It is worth noting that stem cell-based approaches for olfactory regeneration have been extensively explored in preclinical and translational settings. Rodent and other experimental models of chemically or surgically induced anosmia have demonstrated that MSCs, olfactory ensheathing cells, and nasal epithelial progenitors can promote epithelial repair and behavioral recovery, providing a solid mechanistic and translational foundation for future clinical application[9,11,15-20] (Table 1). Taken together, this milestone study by Ni et al[14] provides the first robust, long-term pediatric clinical evidence supporting stem cell-based therapy for CODs, establishing both safety and sustained functional recovery over three years (Figure 1).

Figure 1 Schematic representation of autologous nasal epithelial stem cell transplantation and long-term follow-up in children with congenital olfactory disorders. The figure was created with Figdraw.

Table 1 Representative animal and early experimental studies investigating cell-based interventions for olfactory dysfunction.

Ref.	Cell type	Study model	Route of administration	Evaluation period	Main outcome
Kurtenbach et al[15], 2019	c-KIT(+) globose basal cells (olfactory progenitors)	Mouse (hyposmia model)	Intranasal droplet delivery	3-4 weeks (EOG/histology); 8-10 weeks (behavior)	Intranasally delivered c-KIT(+) progenitors generated olfactory neurons and restored function
Jiang et al[16], 2025	Human olfactory neurospheres	Mouse (methimazole-induced hyposmia)	Intranasal delivery	4 weeks (histology/behavior)	DNS-ONS showed superior regenerative capacity and function restoration compared to CRS-ONS
Ishikura et al[11], 2023	Mouse ADSCs	Mouse (methimazole-induced OE damage)	Nasal administration	14 days [histology (aversion test)]	ADSCs promote OE regeneration (OMP increase) and support the recovery of odor aversion behavior
Kim et al[17], 2009	Rat ADSCs	Rat (olfactory nerve transection)	Intravenous injection	30 days (histology)	Systemic ADSCs promote OE regeneration (OMP/PCNA increase) following nerve transection
Franceschini et al[18], 2014	Human ADSCs	Mouse (dichlobenil-induced OE lesion)	Tail vein injection	30 days and 60 days (EOG/histology)	Human ADSCs engraft, induce OE regeneration, and restore functional reactivity (EOG)
Hazir et al[19], 2025	NSCs	Mouse (3-MI-induced anosmia)	Intranasal delivery	2 weeks (early histology); 4 weeks [histology/behavior (FFT)/PCR]	NSCs transplantation promotes functional recovery (FFT) and OE epithelial repair
Lee et al[9], 2010	NSCs	Mouse (3-MI-induced anosmia)	Intranasal delivery	4 weeks [histology/behavior (FFT)/western blot]	NSCs transplantation promoted recovery of olfactory function and improved survival
Jo et al[20], 2015	BMSCs	Rat (TX-100-induced OE damage)	Direct OE injection	2 weeks and 4 weeks [histology/behavior (FFT)/IHC/qRT-PCR]	BMSCs transplantation promoted OE and olfactory function restoration, associated with NGF and BDNF regulation

EOG: Electro-olfactogram; DNS: Deviated nasal septum; ONS: Olfactory neurospheres; CRS: Chronic rhinosinusitis; ADSCs: Adipose-derived stem cells; OE: Olfactory epithelium; OMP: Olfactory marker protein; PCNA: Proliferating cell nuclear antigen; NSCs: Neural stem cells; 3-MI: 3-methylindole; FFT: Fast Fourier transform; PCR: Polymerase chain reaction; IHC: Immunohistochemistry; qRT-PCR: Quantitative real-time polymerase chain reaction; BMSCs: Bone marrow-derived mesenchymal stem cells; NGF: Nerve growth factor; BDNF: Brain-derived neurotrophic factor.

The study provides rare longitudinal evidence of recovery in CODs. The combination of functional gains, quality of life improvement, and reassuring safety profile underscores the therapeutic potential of NESCs. Importantly, the morphological and electrophysiological findings suggest not only symptomatic relief but also structural repair of the olfactory mucosa. To put these findings into context, the demonstration of three-year functional recovery in CODs contrasts with most prior attempts at sensory neural regeneration, such as in retinal or auditory systems, which have shown only partial or transient benefits[21,22]. By contrast, Ni et al[14] provide the first durable, longitudinal evidence in a pediatric sensory disorder.

Despite these promising results, key limitations restrict generalizability. The absence of a randomized control arm and the modest sample size are consistent with challenges faced across early-stage neural cell therapy trials. Similar issues were observed in Parkinson’s disease stem-cell transplantation studies, where small, open-label cohorts initially suggested efficacy, but randomized trials tempered expectations[23,24]. These precedents highlight why multicenter randomized controlled trials are indispensable before this therapy can be considered standard of care[25]. Future controlled studies should further refine inclusion criteria, optimize transplantation protocols, and ensure extended follow-up for pediatric safety. These trials should refine inclusion criteria such as age and residual olfactory function, optimize dosing and transplantation protocols, and include rigorous safety endpoints. Extended long-term monitoring beyond three years will be critical, especially in children, to capture rare or delayed adverse effects.

Mechanistically, it remains unclear whether olfactory recovery results from neuronal replacement, paracrine signaling, or niche reactivation. Current evidence suggests that the beneficial effects of NESC transplantation may be largely driven by paracrine actions. Transplanted olfactory-supporting cells and MSCs have been shown to secrete neurotrophic and immunomodulatory factors (e.g., nerve growth factor, brain-derived neurotrophic factor, glia cell line-derived neurotrophic factor, ciliary neurotrophic factor) that enhance neuronal survival, progenitor proliferation, and synaptic reconnection in injured olfactory systems[26,27]. Moreover, olfactory-mucosa-derived MSC populations produce extracellular vesicles (exosomes) with demonstrated immunomodulatory and reparative effects in vivo[28,29]. These findings not only underscore paracrine trophic/immunomodulatory actions as plausible contributors to the observed functional recovery but also motivate the exploration of cell-free approaches (secretome/exosome preparations) as potentially less invasive, mechanistically relevant alternatives - particularly attractive for pediatric application.

Recent single-cell genomic and transcriptomic studies have shown the potential to delineate cellular plasticity and regenerative capacity[30], providing a framework for dissecting these mechanisms in future work. Elucidating these biological processes will be critical for optimizing therapeutic strategies and predicting long-term safety. Recent single-cell transcriptomic studies of human olfactory epithelium revealed profound aging-associated stem cell alterations, implicating niche dysfunction as a central barrier to regeneration[31,32]. In parallel, mechanistic studies using animal models, organoid systems, and advanced imaging are indispensable to clarify how regeneration is achieved and how grafted cells behave over time. For instance, in vivo two-photon microscopy provides high-resolution, non-invasive tracking of cell dynamics in living tissues, offering a powerful tool for monitoring graft behavior[33]. In addition, nasal and olfactory organoids have been successfully established to model epithelial differentiation and to test regenerative cues, thereby providing a complementary platform to de-risk future human trials[34]. Integrating such systems into preclinical pipelines would allow mechanistic validation - clarifying whether transplanted cells integrate, secrete trophic factors, or activate endogenous repair - before large-scale pediatric randomized controlled trials. In addition, leveraging recent advances in olfactory stem cell biology, including the roles of horizontal basal cells and globose basal cells in mucosal regeneration and aging-associated remodeling[31], inducible grafting of olfactory epithelial cell populations[35], and nasally delivered mesenchymal or adipose-derived stem cells secreting neurotrophic factors[11], may accelerate improvements in both outcome and feasibility.

FUTURE PERSPECTIVES

Moving forward, translational progress will rely on practical optimization - improving graft survival and integration, engineering biomaterial scaffolds to guide axonal reconnection, and establishing scalable good manufacturing practice-compliant cell manufacturing. Advances in other regenerative fields suggest that paracrine modulation, immune engineering, and biomaterial design often yield synergistic benefits[11,36]. Finally, international collaborative networks will be essential to harmonize regulatory standards, share long-term safety data, and ensure equitable access. Ni et al’s work[14] offers compelling proof-of-concept for olfactory regeneration, marking a pivotal advance in the field. To translate this innovation into reproducible and globally accessible clinical care, future efforts must focus on mechanistic studies using organoid and animal models, alongside rigorous adherence to translational best practices.

CONCLUSION

In summary, Ni et al’s study[14] provides the first durable clinical evidence for stem cell therapy in CODs, redefining a condition long regarded as untreatable. While replication in multicenter trials and deeper mechanistic insights are essential, this work establishes a foundation upon which true therapeutic innovation in sensory regeneration can be built.