Acupuncture in neural stem cell-based therapy for cognitive impairment

Abstract

A central barrier to stem cell-based regenerative therapy for dementia extends beyond the cell product itself to the pathological hippocampal niche, which limits engraftment, proliferation, differentiation, and neural circuit integration. In this context, Li et al recently published a study in World Journal of Stem Cells, and they showed that acupuncture enhances the efficacy of neural stem cell transplantation in SAMP8 mice, resulting in improved learning and memory and attenuation of key Alzheimer-like pathological biomarkers, including Aβ and phosphorylated tau. The mechanistic framework is particularly noteworthy: Acupuncture increased miR-124, a neuron-enriched microRNA that can coordinately regulate Notch and Wnt signaling. Increased miR-124 was associated with reduced aberrant Notch activation and with enhanced canonical Wnt/β-catenin and non-canonical Wnt/Ca²⁺ signaling, with convergence on cyclin D1 to promote neural stem cell proliferation, reduce apoptosis, and enhance differentiation toward neuronal and glial phenotypes. These findings support a “microenvironment-first” strategy in which cell therapy is paired with targeted neuromodulation to improve graft performance. Key next steps include standardizing acupuncture protocols as a therapeutic product, incorporating molecular potency assays based on miR-124/Notch/Wnt signatures, and evaluating the long-term safety and durability of circuit-level benefits.

Key Words: Acupuncture; Neural stem cell; miR-124; Notch1; Wnt/β-catenin; Alzheimer’s disease; Neuromodulation

Core Tip: Dementia is a heterogeneous syndrome in which hippocampal circuit dysfunction is driven, in part, by a hostile microenvironment that compromises grafted neural stem cell (NSC) survival and fate determination. Li et al described a niche-licensing strategy in which acupuncture improves the hippocampal milieu and enhances the efficacy of transplanted NSCs through upregulation of the neuron-enriched miR-124. Increased miR-124 suppresses aberrant Notch signaling while restoring Wnt activity, thereby rebalancing the Notch/Wnt axis, modulating cyclin D1-related cell-cycle dynamics, and promoting NSC proliferation and neuronal differentiation. These effects attenuate Alzheimer-like pathology and improve cognitive function in SAMP8 mice, supporting acupuncture as a promising regenerative neuromodulatory strategy for dementia.

This editorial refers to “Acupuncture improves transplanted neural stem cells in dementia mice by modulating hippocampal microenvironment via microRNA-124 mediated Notch and Wnt pathways” by Li et al, 2026; https://doi.org/10.4252/wjsc.v18.i3.114929.

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INTRODUCTION

Dementia is not a single disease but a clinical syndrome arising from diverse neuropathologies, including Alzheimer-type pathology, vascular injury, Lewy body disease, and mixed etiologies. Its societal burden continues to grow, and prevention frameworks increasingly incorporate brain health, risk reduction, and integrated care systems[1,2]. However, even the most effective prevention strategies do not fully address patients with established dementia, in whom neuronal loss, synaptic disconnection, neuroinflammation, vascular dysfunction, and impaired neurogenesis converge to undermine circuit function[3,4].

NSC transplantation remains conceptually attractive because it may support repair through cell replacement, trophic support, and modulation of the host microenvironment. Reviews of stem cell-based approaches in neurodegeneration have emphasized that therapeutic benefit is mediated not only by direct neuronal replacement but also by paracrine signaling and niche interactions[5]. In parallel, stem cell-derived extracellular vesicles (EVs) are gaining momentum as a “cell-free” strategy that may reduce immunogenicity and logistical barriers while preserving neuroprotective signaling capacity[5,6]. Critically, this paracrine mechanism underscores that the therapeutic effects of transplanted stem cells may extend well beyond direct cell replacement. Grafted cells can serve as dynamic in situ sources of EVs and trophic factors, potentially offering sustained advantages over one-time EV administration. However, this potential is constrained by the diseased brain niche, where inflammatory signaling, altered developmental pathways, and metabolic stress limit survival and guided differentiation.

In a recent issue of the World Journal of Stem Cells, Li et al[7] addressed this bottleneck by using acupuncture to reprogram the hippocampal microenvironment and by identifying miR-124 as an upstream regulator that coordinates developmental signaling pathways governing stem cell fate. miR-124 is among the most abundant microRNAs in the brain and plays broad roles in neuronal differentiation and neural homeostasis; its dysregulation has been implicated across multiple neurodegenerative contexts[8]. The authors propose that acupuncture shifts the hippocampal niche toward a pro-repair state by elevating miR-124, thereby dampening Notch hyperactivity while restoring Wnt signaling—two pathways that often function as opposing “brakes” and “accelerators” of NSC activation and differentiation.

How the dementia-associated hippocampal niche impairs stem cell therapy

Hippocampal dysfunction is a core feature of many forms of dementia, as this region lies at the intersection of memory encoding, stress regulation, and plasticity. Adult hippocampal neurogenesis persists in mammals and is linked to specific cognitive functions; accumulating evidence suggests that it declines with aging and is disrupted in dementia-relevant pathology[9]. In practice, transplantation is not simply a matter of “adding cells” to restore function. Transplanted NSCs must survive, proliferate appropriately, differentiate into functional lineages, and integrate into existing circuits. Each of these steps is shaped by the surrounding microenvironment.

Li et al[7] used the SAMP8 mice, which are widely employed as a model of age-associated cognitive impairment with neuroinflammatory and neurodegeneration-relevant features. Recent reviews have highlighted that SAMP8 mice exhibit deficits in hippocampus-dependent tasks, such as the Morris water maze, as well as alterations in inflammation, neurogenesis, and neuronal integrity, making this model useful for mechanistic studies, albeit still an imperfect proxy for human dementia[10]. Importantly, the Morris water maze—used in the present study—remains a validated tool for assessing hippocampus-dependent learning and memory, although its interpretation requires caution because of potential stress-related, sensorimotor, and protocol-related confounders[11].

Li et al[7] directly addressed the niche problem by administering acupuncture both before and after transplantation. They then evaluated not only cognition but also biochemical markers, lineage markers (Nestin, NeuN, and GFAP), and signaling pathway readouts. This multi-level design is a strength, as it links behavioral outcomes to plausible cellular programs rather than relying on a single endpoint.

miR-124 as a “coordination signal” linking Notch and Wnt fate programs

The conceptual advance of this work lies in treating miR-124 not merely as a marker, but as a regulatory node capable of coupling distinct developmental pathways. miR-124 has been widely reviewed as a therapeutic target in central nervous system injury and disease, with key roles in neuronal differentiation and circuit stability[8]. Given the broader literature showing that Notch and Wnt crosstalk can enforce robust cell-fate decisions—often in a Notch-ON/Wnt-OFF configuration—and that perturbation of either pathway can alter stem cell pool maintenance[12], the proposed mechanism is biologically plausible.

In the adult brain, Notch signaling is often associated with maintaining stem/progenitor quiescence or restricting neuronal differentiation, whereas Wnt/β-catenin signaling is more commonly linked to proliferative and neurogenic programs, although both pathways are highly context dependent. Li et al[7] found that elevation of miR-124 was associated with reduced Notch pathway readouts and restored Wnt signaling. This observation is consistent with a model in which inhibitory Notch signaling is reduced while pro-neurogenic Wnt signaling is restored, although it is important not to oversimplify the biology: Wnt signaling is heterogeneous, involving canonical and non-canonical pathways, and is also cell-type specific, acting in endothelial, neuronal, and glial compartments. For example, Wnt/β-catenin activity in the brain endothelium has been implicated in blood-brain barrier integrity in Alzheimer’s disease-relevant pathology, underscoring that “Wnt restoration” may carry vascular as well as neurogenic significance[13].

FROM PATHWAYS TO CELL CYCLE: CYCLIN D1 AS A CONVERGENCE READOUT AND ITS IMPLICATIONS

Li et al[7] identified cyclin D1 as a functional convergence node through which Notch and Wnt signaling intersect with cell-cycle control. This is a reasonable strategy, as cyclin D1 is central to G1/S transition and can indicate whether stem/progenitor populations are entering proliferative states. The authors further employed a brain-slice/NSC coculture system combined with flow cytometry, adding mechanistic specificity beyond bulk tissue assays.

However, cyclin D1 is also a double-edged translational marker. In regenerative settings, increased cell-cycle entry may reflect repair potential, but in a chronically stressed brain, dysregulated cycling may also signal maladaptive responses, lineage mis-specification, or even oncogenic risk if extrapolated to clinical settings without appropriate safeguards. Li et al’s data[7] suggest shifts in lineage-marker profiles, including changes in Nestin, NeuN, and GFAP, which partly alleviate the concern that the observed effect reflects only increased cell cycling rather than productive lineage progression (Figure 1). Even so, durability and functional integration remain the central issues. Dementia is fundamentally a circuit disorder stemming from neuronal injury or death, and the most compelling endpoints would therefore include long-term electrophysiological integration, synaptic connectivity, and circuit-level rescue, rather than marker shifts alone. The present results provide a strong rationale for pursuing these next steps, rather than conclusively establishing them.

Figure 1 Schematic summary of the integrative interpretation of Li et al’s study[7]. Acupuncture is positioned as a niche-modulating input that raises miR-124, dampens Notch hyperactivation, restores Wnt signaling, and shifts cyclin D1-linked cell-cycle dynamics to support proliferation/differentiation and circuit repair. NICD: Notch intracellular domain; NSCs: Neural stem cell.

The neuromodulation landscape in dementia

To place acupuncture-assisted niche remodeling in a broader therapeutic context, it is useful to consider how other neuromodulation strategies have been applied to regulate brain function in dementia. These approaches differ in their physical modes of delivery and proximal targets, but can be grouped according to their dominant biological effects. Photobiomodulation is commonly linked to metabolic, mitochondrial, and neurovascular signaling[14]. Electrical stimulation modalities, such as transcranial direct current stimulation and transcranial alternating current stimulation, and magnetic stimulation, such as repetitive transcranial magnetic stimulation, primarily modulate cortical excitability, oscillatory dynamics, and neural circuit plasticity[15,16]. Transcranial focused ultrasound, by contrast, offers the possibility of deeper and more spatially confined engagement, albeit with dose-dependent constraints[17]. Against this backdrop, acupuncture may represent a distinctive modality with the potential to influence the hippocampal niche through neuromodulatory signaling, thereby complementing other strategies by improving the regenerative permissiveness of the brain microenvironment—an advantage highlighted by the work of Li et al[7] in the context of NSC-based therapy (Table 1). These distinctions also suggest potential therapeutic complementarity. Acupuncture may preferentially enhance regenerative permissiveness, raising the possibility that rational combinations with other neuromodulatory approaches could amplify or prolong benefit[18-33].

Table 1 Comparison of neuromodulation modalities relevant to brain-function regulation.

Modality	Core physical carrier	Typical biological “entry points”	Strengths for dementia-relevant brain regulation	Key constraints/risks
Photonic, e.g., photobiomodulation	Light (red/NIR)	Mitochondrial cytochrome c oxidase, redox signaling, cerebral blood flow	Non-invasive; potential metabolic and vascular effects; clinically scalable	Uncertain dose window; limited tissue penetration; heterogeneous protocols[18-20]
Electrical, e.g., tDCS/tACS	Electric fields/currents	Membrane polarization, oscillatory entrainment	Low cost; portable; growing evidence base from RCTs and meta-analyses in cognitive impairment/dementia	Variable field delivery; modest effect sizes; placebo sensitivity; montage heterogeneity[21-23]
Magnetic, e.g., rTMS	Magnetic pulses inducing electric fields	Cortical excitability, circuit plasticity	Can target circuits; clinical infrastructure exists	Protocol variability; challenging sham-controlled designs; mixed durability of effects[24-26]
Acoustic, e.g., transcranial ultrasound stimulation	Focused ultrasound pressure waves	Mechanosensitive channels	Deep targeting capability; emerging precision and focality	Safety standards still evolving; parameter sensitivity; limited clinical data[27-29]
Acupuncture	Mechanical stimulation at acupoints; afferent nerve activation	Afferent nerve activation; peripheral-central neuroimmune and autonomic pathways; local niche modulation (e.g., miR-124/Notch-Wnt signaling)	Engages whole-body systems; modulates inflammation and metabolism; suitable for repeated dosing; potential to prime stem-cell niche	Protocol heterogeneity; blinding difficulties; need for rigorous mechanism-based controls[30-33]

NIR: Near-infrared; tDCS: Transcranial direct current stimulation; tACS: Transcranial alternating current stimulation; RCT: Randomized controlled trial; rTMS: Repetitive transcranial magnetic stimulation.

LIMITATIONS AND FUTURE PERSPECTIVES

First, the generalizability of these findings across dementia etiologies remains uncertain. SAMP8 mice are valuable for mechanistic exploration of age-accelerated cognitive impairment and dementia-relevant hippocampal changes, but this model cannot capture the clinical heterogeneity of human dementia, in which mixed pathologies—including vascular injury, proteinopathies, and neuroimmune phenotypes—often coexist and evolve over many years[10]. The study’s strong internal logic—upregulation of miR-124 and cyclin D1, downregulation of Notch, restoration of Wnt signaling, and consequent cognitive improvement—may nevertheless depend on model-specific baseline states. A more translationally informative approach would test whether the same miR-124-Notch/Wnt coupling emerges across multiple dementia-relevant contexts, such as vascular cognitive impairment models, synucleinopathy models, or mixed-pathology models, and whether the “niche-normalizing” effect of acupuncture persists when pathology is driven by non-amyloid mechanisms. The work would also benefit from deeper circuit-level endpoints, as long-term synaptic integration and network function, assessed by electrophysiology and connectivity metrics, are more proximate to dementia-related disability than marker changes alone.

Second, intervention specificity and durability require more rigorous definition. Acupuncture studies face well-recognized challenges related to blinding and to disentangling specific acupoint effects from nonspecific handling or stimulation controls. Li et al[7] included non-acupoint comparators, which strengthens the inference, but future studies should quantify how much of the benefit is attributable to: (1) Stress modulation; (2) Systemic immune regulation; (3) Local hippocampal pathway shifts; or (4) Direct effects on transplanted cells. At the molecular level, miR-124 is pleiotropic; although its elevation may promote neuronal differentiation, it may also affect non-neuronal compartments, including microglia and endothelium, in ways that are relevant to dementia progression[8]. Finally, the field is increasingly exploring NSC-derived EVs as alternatives or adjuncts to cell transplantation. Combining acupuncture with EV-based strategies may help determine whether the niche-priming concept extends beyond graft survival to more scalable and potentially lower-risk therapeutic platforms[34].

CONCLUSION

Interest in integrating acupuncture into dementia care has grown in China and other countries, supported by expanding clinical programs and research initiatives[35-39]. Some clinical studies have reported that acupuncture may improve cognitive measures, such as Mini-Mental State Examination and Montreal Cognitive Assessment scores, as well as activities of daily living in patients with dementia, with an acceptable safety profile and possible additive effects when combined with conventional pharmacotherapy such as donepezil[40-42]. In this context, Li et al[7] present a mechanistically coherent framework in which acupuncture enhances the performance of transplanted NSCs in a dementia mouse model by increasing miR-124 and thereby coordinating Notch suppression with Wnt restoration, converging on cyclin D1-linked programs of cell-cycle regulation and differentiation. The editorial significance of this study lies in its niche-control thesis: Successful repair in dementia may depend not only on the therapeutic modality itself, but also on whether the intervention can shift the hippocampal microenvironment into a state permissive for regeneration. This work identifies a plausible molecular control point—miR-124—that links systemic neuromodulation to local developmental signaling and defines clear priorities for translation, including cross-etiology validation, circuit-level functional integration, durability testing, and careful dissection of specific effects vs broader neuroimmune influences.