Advances in the Application of Pluripotent Stem Cells in the Research and Treatment of Neurological Diseases

1. Introduction

Neurological diseases are a major cause of death and disability worldwide, and their global burden continues to rise, largely due to population aging, environmental changes, metabolic disorders, and lifestyle factors [1]. Despite decades of research, most treatments remain pharmacological and primarily provide symptomatic relief. Traditional drug therapy faces significant challenges: (1) heterogeneous etiologies hinder targeted intervention, often causing off-target effects [2]; (2) the blood-brain barrier limits drug delivery and individual variability affect outcomes [3]; and (3) long-term medication can lead to severe adverse effects [4]. Therefore, innovative and precise therapeutic strategies are urgently needed.

In recent years, pluripotent stem cells (PSCs) have emerged as a promising platform for neurological disease research and treatment because of their self-renewal and multidirectional differentiation capabilities. Unlike totipotent stem cells, PSCs cannot form a complete organism but can be derived from somatic cells through induced pluripotent stem cell (iPSC) technology, avoiding ethical concerns and enabling controlled differentiation. These properties support wide applications in regenerative medicine, disease modeling, and drug discovery.

In the treatment of neurological diseases, PSC-based transplantation offers distinct advantages over conventional pharmacotherapy: (1) PSCs can be precisely directed to differentiate into specific neuronal or glial subtypes using gene-editing technologies, thereby minimizing side effects and enhancing therapeutic efficacy [5]; and (2) PSCs can be integrated with drug delivery systems to achieve more accurate, targeted interventions [6]. Furthermore, PSCs enable the establishment of physiologically relevant disease models, facilitate mechanistic studies, and support the preclinical safety assessment of novel therapeutics. At present, clinical trials investigating PSC-based interventions have been initiated for several neurological disorders, including Parkinson’s disease, spinal cord injury, epilepsy, and amyotrophic lateral sclerosis.

This review summarizes recent advances in PSC applications for neurological disorders, emphasizing roles in regeneration, disease modeling, and personalized therapy, and explores future clinical translation.

1.1. Types and preparation of PSC

PSC possess self-renewal and multilineage differentiation capabilities, enabling the generation of specialized cell types for regenerative medicine and personalized therapy. Major PSC sources include embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and expanded potential stem cells (EPSCs). Among these, iPSCs are particularly valued for their derivation from somatic cells, avoidance of ESC-related ethical issues, large-scale expansion potential, and suitability for autologous transplantation, reducing immune rejection [7, 8]. MSCs, as a non-embryonic stem cell source, have been extensively applied in neurological disease research and therapy due to their immunomodulatory and neuroprotective properties [9]. EPSCs, characterized by broader developmental potential and superior neural differentiation capacity, have emerged as a promising cell type for treating neural injuries and neurodegenerative disorders [10].

At present, approaches for reprogramming somatic cells into iPSCs include: (1) the ectopic expression of transcription factors-classically Oct3/4, Sox2, Klf4, and c-Myc (OSKM) [11]; (2) microRNA-mediated induction, such as the combined action of miRNA302/367 with HDAC2 modulation [12]; and (3) chemical reprogramming using small molecules such as VC6T and forskolin (FSK) [13].

Initially, iPSC generation relied on integrating reprogramming genes into the host genome via viral vectors, including retroviruses [11]. With technological advancements, non-viral delivery systems have increasingly become the preferred approach. For example, reprogramming factors can be introduced by direct RNA delivery through electroporation, by cationic carriers facilitating RNA transfection, or via cell-penetrating peptides (CPPs) enabling efficient intracellular protein delivery [14-16]. Compared with viral vectors, non-viral systems reduce the risk of insertional mutagenesis and host immune activation, thereby improving safety profiles [17]. Nonetheless, these approaches still face limitations such as relatively low delivery efficiency and prolonged reprogramming timelines [18].

Chemical reprogramming represents an attractive alternative, offering greater flexibility and precise temporal-spatial regulation of gene expression compared with transgene-based strategies. Small molecules, including vitamin C, CHIR99021, and FSK can modulate signaling pathways and epigenetic states to guide cell fate transitions with high controllability, thus enhancing clinical translation potential [13, 19, 20]. Given the ease of combination and adjustment, small-molecule cocktails hold particular promise for generating clinically relevant, lineage-specific cell types tailored for therapeutic applications.

1.2. Alzheimer's disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by beta-amyloid (Aβ) deposition, neurofibrillary tangles (NFTs), and neuronal loss [21]. Current therapies, including acetylcholinesterase inhibitors, NMDA antagonists, and anti-Aβ antibodies, offer only symptomatic relief without altering disease progression [22].

The development of iPSCs technology has provided new possibilities for AD modeling and treatment. Over the past 15 years, iPSC-based models have evolved from simply recapitulating pathological hallmarks to enabling detailed exploration of disease mechanisms and therapeutic target identification. Early models generated from fibroblasts of early-onset familial AD patients carrying Presenilin 1 (PS1) and Presenilin 2 (PS2) mutations successfully reproduced disease-specific phenotypes and served as platforms for candidate drug validation [23]. Advances in 3D culture improved fidelity: neural stem cell cultures replicate Aβ plaques and tau pathology [24], and brain organoids exposed to human serum exhibit AD-like features [25]. Patient-derived organoids display Aβ aggregation and tau hyperphosphorylation, which β- and γ-secretase inhibitors can attenuate, supporting their value in preclinical studies [26].

iPSC models have revealed multiple AD-related pathways. Aberrant APP processing activates GSK-3β and promotes tau hyperphosphorylation [27]; APP V717I mutation elevates tau and Aβ species [28]; MAPT mutations accelerate neuronal maturation and excitability, driving tau accumulation [29]; and APP/PS1 mutations increase the Aβ42/Aβ40 ratio and reduce synaptic proteins, with homozygous APP variants producing severe phenotypes [30].

iPSC-derived neurons support high-throughput drug screening, enabling assays to identify compounds reducing Aβ toxicity [31]. Large-scale screens using patient-derived neurons have revealed synergistic drug combinations, including bromocriptine, sodium cromoglicate, and topiramate, which enhance anti-Aβ activity [32].

In terms of transplantation therapy, transplantation of iPSC-derived cells into 5XFAD transgenic AD mice has significantly improved cognitive performance, potentially via plaque reduction and differentiation of grafted cells into oligodendrocytes [33]. Table 1 provides a summary of recent advances in iPSC-derived models for Alzheimer’s disease, highlighting their roles in disease modeling, mechanistic studies, and therapeutic development.

Overall, iPSC technology holds considerable promise for advancing AD research and therapy. Future directions include optimizing model stability, improving the fidelity of disease recapitulation, and integrating gene editing with high-throughput screening to accelerate the development of effective interventions.

Table 1. iPSC-based models for Alzheimer’s disease research
Disease Type	Stem Cell Type	Research Stage	Cell Source	Key Findings	Reference
Alzheimer’s disease	iPSCs	In vitro	Human	Established an iPSC-based model recapitulating key AD pathological mechanisms, applied for candidate drug screening.	[8]
Alzheimer’s disease	iPSCs	In vitro	Human	Reproduced Aβ aggregation and Tau hyperphosphorylation; confirmed that β- and γ-secretase inhibitors significantly reduced these pathologies, demonstrating potential for drug development.	[11]
Alzheimer’s disease	iPSCs	In vitro	Human	MAPT gene mutations accelerate neuronal maturation and increase excitability, thereby promoting abnormal Tau accumulation.	[14]
Alzheimer’s disease	iPSCs	In vitro	Human	APP and PS1 mutations increase the Aβ42/Aβ40 ratio and reduce synaptic protein levels; homozygous APP mutations cause more severe pathology.	[15]
Alzheimer’s disease	iPSCs	In vitro	Human	Large-scale drug screening in patient-derived iPSC neurons identified a combination of bromocriptine, sodium cromoglicate, and topiramate with enhanced anti-Aβ effects.	[17]
Alzheimer’s disease	iPSCs	In vivo	Mouse	Reprogrammed mouse fibroblasts into iPSCs and transplanted them into 5XFAD AD mouse brains, significantly improving cognitive deficits, likely via Aβ plaque reduction and differentiation into oligodendrocytes.	[18]

2.3 Parkinson's disease

Parkinson’s disease (PD) is marked by dopaminergic neuron (DAn) loss in the substantia nigra and α-synuclein (α-syn) aggregation into Lewy bodies [34]. It manifests with motor symptoms—tremor, rigidity, bradykinesia, postural instability—and non-motor features such as constipation, sleep disturbances, and depression [35]. Current therapies, including dopamine replacement (levodopa, MAO-B inhibitors, dopamine agonists), deep brain stimulation, and rehabilitation, alleviate symptoms but do not halt progression or effectively address non-motor deficits [36–39].

iPSC technology models PD pathologies, supporting mechanistic studies and drug discovery. SNCA triplication-derived iPSCs reproduce α-syn accumulation, oxidative stress, and stressor sensitivity [40,41]. Gene editing enables isogenic controls for variant-specific analyses [42]. iPSC-derived DAn with LRRK2 p.G2019S mutations show elevated α-syn and stress-response gene expression [43]. Midbrain-like organoids (hMBOs) from SNCA triplication iPSCs exhibit age-dependent α-syn aggregation and progressive DAn loss [44].

iPSC models have revealed multiple pathogenic mechanisms of PD. For instance, The A53T SNCA mutation impairs mitochondrial function, increases reactive oxygen species (ROS) production, suppresses the MEF2C-PGC1α pathway, and triggers neuronal apoptosis [45]. Overexpression of α-syn can activate the IRE1α/XBP1-mediated unfolded protein response (UPR), elevating the pro-apoptotic factor CHOP [46]. Both SNCA triplication and A53T mutations are associated with α-syn oligomerization, cholesterol metabolism deficits, and endoplasmic reticulum stress [47]. Other PD-associated mutations, such as those in LRRK2, PINK1/Parkin, GBA, and VPS35-are linked to synaptic dysfunction, mitochondrial impairment, and defective protein degradation [48-52].

iPSC-derived DAn transplantation has shown promising therapeutic potential in preclinical studies. In rodent models, the extent of neurite extension into the host striatum has been identified as a critical determinant of graft efficacy, with REST gene expression proposed as a biomarker for optimal transplantation timing [53]. Additionally, dopamine fiber density post-transplantation has emerged as a predictive marker for functional recovery, informing the design of ongoing and planned clinical trials [54]. Table 2 outlines key studies utilizing iPSC technology for Parkinson’s disease.

Table 2. iPSC-based models for parkinson’s disease research
Disease Type	Stem Cell Type	Research Stage	Cell Source	Key Findings	Reference
Parkinson’s disease	iPSCs	In vitro (cell model)	Human	iPSC-derived dopaminergic neurons (DAn) from SNCA triplication patients reproduced α-synuclein accumulation, increased oxidative stress, and hypersensitivity to stressors.	[26]
Parkinson’s disease	iPSCs	In vitro (cell model)	Human	DAn derived from iPSCs carrying the LRRK2 p.G2019S mutation exhibited elevated α-syn expression and upregulation of stress-response genes.	[28]
Parkinson’s disease	iPSCs	In vitro (cell model)	Human	Both SNCA triplication and A53T mutation in DAn led to α-syn oligomerization, cholesterol metabolism defects, and endoplasmic reticulum stress.	[32]
Parkinson’s disease	iPSCs	In vitro (mechanistic)	Human	Mutations in LRRK2, PINK1/Parkin, GBA, and VPS35 are closely associated with synaptic dysfunction, mitochondrial impairment, and abnormal protein degradation.	[33–37]
Parkinson’s disease	iPSCs	In vivo (transplantation)	Human	The extent of neurite outgrowth into the host striatum was a key factor influencing transplantation outcomes; REST gene expression could serve as an indicator for optimal transplantation timing.	[38]
Parkinson’s disease	iPSCs	In vivo (transplantation)	Human	Dopaminergic fiber density was identified as an important predictor of transplantation efficacy, facilitating the development of related clinical trial plans.	[39]

2.4 Spinal cord injury

Spinal cord injury (SCI) is a debilitating central nervous system disorder caused severe sensory, motor, and autonomic deficits, with high disability and socioeconomic burden [55]. Current treatments-pharmacological therapy, decompression surgery, and rehabilitation—mainly alleviate symptoms without restoring full function.

iPSC-based strategies show promise for SCI repair. iPSC-derived neural progenitors (NPCs), neural stem cells (NSCs), and oligodendrocyte progenitors (OPCs) promote remyelination, axonal regeneration, and synaptic reconstruction [56,57]. Preclinical studies report region-specific NPCs enhance motor recovery in mice, while cannabinoid receptor activation improves OPC myelination efficiency [56].

In rat models, transplanted iPSC-derived NPCs differentiate in vivo into neurons and astrocytes, establishing functional synaptic networks [58]. Combined with rehabilitation, grafted NSCs boost synaptic activity, secrete neurotrophic factors, and improve motor recovery [59]. Synergistic effects have also been observed with combinatorial transplantation strategies for example, co-delivery of brain-derived neurotrophic factor (BDNF) overexpressing mesenchymal stem cells and iPSC-derived motor neuron precursors (iMNPs) significantly promotes axonal regeneration and functional recovery in chronic SCI models [60].

In terms of neural circuit reconstruction, iPSC-derived pyramidal neuron precursors (PNPs) can form synaptic connections with host neurons post-transplantation while exerting anti-inflammatory effects that improve the local immune milieu [61]. Furthermore, composite constructs, such as TrkC-modified NSCs with aligned collagen scaffolds, further improve motor function and matrix remodeling [62].

Table 3 summarizes iPSC-based SCI interventions and combinatorial strategies. Future directions include integrating iPSC transplantation with biomaterials, gene editing, and exosome engineering to accelerate clinical translation.

Table 3. iPSC-based strategies for spinal cord injury treatment
Disease Type	Stem Cell Type	Research Stage	Cell Source	Key Findings	Reference
Spinal cord injury	iPSCs	In vivo (animal model)	Human	iPSC-derived neural progenitor cells (NPCs) with spinal cord region specificity significantly promoted motor function recovery in moderate SCI models. iPSC-derived OPCs showed enhanced myelination efficiency after CB1R and CB2R activation.	[41]
Spinal cord injury	iPSCs	In vivo (animal model)	Human	Transplantation of iPSC-derived NPCs promoted in vivo differentiation into neurons and astrocytes and facilitated the formation of functional synaptic networks.	[43]
Spinal cord injury	iPSCs	In vivo (animal model)	Human	When combined with rehabilitation training, transplanted NS/PCs enhanced synaptic activity, secreted neurotrophic factors, improved cell survival and differentiation, and promoted motor function recovery.	[44]
Spinal cord injury	iPSCs	In vivo (animal model)	Human	Co-transplantation of brain-derived neurotrophic factor (BDNF)-overexpressing engineered mesenchymal stem cells with iPSC-derived motor neuron progenitors (iMNPs) demonstrated synergistic effects on axonal regeneration and motor function improvement in chronic SCI models.	[45]
Spinal cord injury	iPSCs	In vivo (animal model)	Human	iPSC-derived pyramidal neuron progenitors (PNPs) formed synaptic connections with host neurons after transplantation and exhibited anti-inflammatory properties, improving the local immune microenvironment.	[46]
Spinal cord injury	iPSCs	In vivo (animal model)	Human	A composite tissue engineered by combining TrkC-modified NSCs with linearly aligned collagen scaffolds effectively improved motor function, promoted synapse formation, and facilitated extracellular matrix remodeling in SCI rats.	[47]

3. Conclusion

At present, Conventional treatment modalities for neurological diseases-pharmacotherapy, surgery, and rehabilitation are hindered by intrinsic limitations. Pharmacological approaches often suffer from low delivery efficiency, poor target specificity, and systemic side effects; surgical interventions are applicable to a narrow patient subset and carry procedural risks; rehabilitation primarily serves as an adjunctive measure, with variable efficacy across individuals.

The advent of iPSC technology has created unprecedented opportunities for both research and therapy in neurological disorders. iPSCs can replace lost or damaged neurons, modulate immune responses, promote endogenous repair, and provide neurotrophic support to injured neural circuits [63]. However, several challenges still impede clinical translation, including optimization of cell sourcing and differentiation protocols, refinement of delivery systems, and mitigation of safety concerns such as tumorigenicity and immune rejection.

Currently, most findings are derived from preclinical animal models, and there remains a paucity of validation from large-scale, multi-center clinical trials. Given the multifactorial pathogenesis of neurological diseases, single-modality therapies are unlikely to achieve optimal outcomes. Multimodal strategies-combining iPSC transplantation with gene editing, neuroprotective pharmacotherapy, rehabilitation, advanced biomaterials, 3D bioprinting, or optogenetic modulation-offer a promising path toward synergistic, multi-targeted interventions.

In the future, the integration of iPSC-based approaches with emerging technologies such as single-cell omics, organoid modeling, and advanced neuroimaging will enable the development of personalized and precision therapies. As iPSC technologies continue to mature, they are poised to play a pivotal role in bridging basic research and clinical application, ultimately transforming the therapeutic landscape for neurological diseases.

References

[1]. Steinmetz, J. D., Seeher, K. M., Schiess, N., Nichols, E., Cao, B., Servili, C. and Dua, T. (2024). Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the global burden of disease study 2021. Lancet Neurology, 23(4), 344–381. https: //doi.org/10.1016/S1474-4422(24)00038-3

[2]. Khan, M. I., Hossain, M. I., Hossain, M. K., Rubel, M. H. K., Hossain, K. M., Mahfuz, A. M. U. B. and Anik, M. I. (2022). Recent progress in nanostructured smart drug delivery systems for cancer therapy: a review. ACS Applied Bio Materials, 5(3), 971–1012. https: //doi.org/10.1021/acsabm.2c00002

[3]. Khawli, L. A. and Prabhu, S. (2013). Drug delivery across the blood–brain barrier. Molecular Pharmaceutics, 10(5), 1471–1472. https: //doi.org/10.1021/mp400170b

[4]. Abdullah, S., Mukherjee, S., Shweta and Debnath, B. (2024). The prevention of multi-drug resistance in cancers through the application of nanotechnology-based targeted delivery systems for combination therapies involving traditional chinese medicine. Pharmacological Research - Modern Chinese Medicine, 10, 100386. https: //doi.org/10.1016/j.prmcm.2024.100386

[5]. Paolini Sguazzi, G., Muto, V., Tartaglia, M., Bertini, E. and Compagnucci, C. (2021). Induced pluripotent stem cells (iPSCs) and gene therapy: a new era for the treatment of neurological diseases. International journal of molecular sciences, 22(24), 13674. https: //doi.org/10.3390/ijms222413674

[6]. Chadarevian, J. P., Davtyan, H., Chadarevian, A. L., Nguyen, J., Capocchi, J. K., Le, L. and Blurton-Jones, M. (2025). Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins. Cell Stem Cell, 32(6), 914-934.e8. https: //doi.org/10.1016/j.stem.2025.03.009

[7]. Kimbrel, E. A. and Lanza, R. (2015). Current status of pluripotent stem cells: moving the first therapies to the clinic. Nature Reviews Drug Discovery, 14(10), 681–692. https: //doi.org/10.1038/nrd4738

[8]. Li, K., Kong, Y., Zhang, M., Xie, F., Liu, P. and Xu, S. (2016). Differentiation of pluripotent stem cells for regenerative medicine. Biochemical and Biophysical Research Communications, 471(1), 1–4. https: //doi.org/10.1016/j.bbrc.2016.01.182

[9]. Zhang, X., Kuang, Q., Xu, J., Lin, Q., Chi, H. and Yu, D. (2024). MSC-based cell therapy in neurological diseases: a concise review of the literature in pre-clinical and clinical research. Biomolecules, 14(5), 538. https: //doi.org/10.3390/biom14050538

[10]. Liu, B., Chen, S., Xu, Y., Lyu, Y., Wang, J., Du, Y. and Deng, H. (2021). Chemically defined and xeno-free culture condition for human extended pluripotent stem cells. Nature Communications, 12(1), 3017. https: //doi.org/10.1038/s41467-021-23320-8

[11]. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676. https: //doi.org/10.1016/j.cell.2006.07.024

[12]. Anokye-Danso, F., Trivedi, C. M., Juhr, D., Gupta, M., Cui, Z., Tian, Y. and Morrisey, E. E. (2011). Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell, 8(4), 376–388. https: //doi.org/10.1016/j.stem.2011.03.001

[13]. Hou, P., Li, Y., Zhang, X., Liu, C., Guan, J., Li, H. and Deng, H. (2013). Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science, 341(6146), 651–654. https: //doi.org/10.1126/science.1239278

[14]. Izadi, E., Mohammadi, S. S., Ganjalikhani Hakemi, M., Eshghi, S., Saremi, L., Saltanatpour, Z. and Hamidieh, A. A. (2025). Current biological, chemical and physical gene delivery approaches for producing induced pluripotent stem cells (iPSCs). European Journal of Pharmacology, 1003, 177786. https: //doi.org/10.1016/j.ejphar.2025.177786

[15]. Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y.-H., Li, H., Lau, F. and Rossi, D. J. (2010). Highly efficient reprogramming to pluripotency and directed differentiation of human cells using synthetic modified mRNA. Cell Stem Cell, 7(5), 618–630. https: //doi.org/10.1016/j.stem.2010.08.012

[16]. Kim, D., Kim, C.-H., Moon, J.-I., Chung, Y.-G., Chang, M.-Y., Han, B.-S. and Kim, K.-S. (2009). Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell, 4(6), 472–476. https: //doi.org/10.1016/j.stem.2009.05.005

[17]. Cerneckis, J., Cai, H., and Shi, Y. (2024). Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications. Signal Transduction and Targeted Therapy, 9, 112. https: //doi.org/10.1038/s41392-024-01809-0

[18]. Zu, H. and Gao, D. (2021). Non-viral vectors in gene therapy: recent development, challenges, and prospects. AAPS Journal, 23(4), 78. https: //doi.org/10.1208/s12248-021-00608-7

[19]. Esteban, M. A., Wang, T., Qin, B., Yang, J., Qin, D., Cai, J., Li, W., Weng, Z., Chen, J., Ni, S., Chen, K., Li, Y., Liu, X., Xu, J., Zhang, S., Li, F., He, W., Labuda, K., Song, Y., Peterbauer, A. and Pei, D. (2010). Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell stem cell, 6(1), 71–79. https: //doi.org/10.1016/j.stem.2009.12.001

[20]. Li, Y., Zhang, Q., Yin, X., Yang, W., Du, Y., Hou, P. and Deng, H. (2011). Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Research, 21(1), 196–204. https: //doi.org/10.1038/cr.2010.142

[21]. Peng, L., Zhang, Z., Li, Q., Song, Z., Yan, C. and Ling, H. (2024). Unveiling the multifaceted pathogenesis and therapeutic drugs of alzheimer’s disease: a comprehensive review. Heliyon, 10(20). https: //doi.org/10.1016/j.heliyon.2024.e39217

[22]. Pardo-Moreno, T., González-Acedo, A., Rivas-Domínguez, A., García-Morales, V., García-Cozar, F. J., Ramos-Rodríguez, J. J. and Melguizo-Rodríguez, L. (2022). Therapeutic approach to alzheimer’s disease: current treatments and new perspectives. Pharmaceutics, 14(6), 1117. https: //doi.org/10.3390/pharmaceutics14061117

[23]. Yagi, T., Ito, D., Okada, Y., Akamatsu, W., Nihei, Y., Yoshizaki, T. and Suzuki, N. (2011). Modeling familial alzheimer’s disease with induced pluripotent stem cells. Human Molecular Genetics, 20(23), 4530–4539. https: //doi.org/10.1093/hmg/ddr394

[24]. Choi, S. H., Kim, Y. H., Hebisch, M., Sliwinski, C., Lee, S., D’Avanzo, C. and Kim, D. Y. (2014). A three-dimensional human neural cell culture model of alzheimer’s disease. Nature, 515(7526), 274–278. https: //doi.org/10.1038/nature13800

[25]. Chen, X., Sun, G., Tian, E., Zhang, M., Davtyan, H., Beach, T. G. and Shi, Y. (2021). Modeling sporadic alzheimer’s disease in human brain organoids under serum exposure. Advanced Science, 8(18), 2101462. https: //doi.org/10.1002/advs.202101462

[26]. Raja, W. K., Mungenast, A. E., Lin, Y.-T., Ko, T., Abdurrob, F., Seo, J., and Tsai, L.-H. (2016). Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate alzheimer’s disease phenotypes. PLOS One, 11(9), e0161969. https: //doi.org/10.1371/journal.pone.0161969

[27]. Israel, M. A., Yuan, S. H., Bardy, C., Reyna, S. M., Mu, Y., Herrera, C. and Goldstein, L. S. B. (2012). Probing sporadic and familial alzheimer’s disease using induced pluripotent stem cells. Nature, 482(7384), 216–220. https: //doi.org/10.1038/nature10821

[28]. Muratore, C. R., Rice, H. C., Srikanth, P., Callahan, D. G., Shin, T., Benjamin, L. N. P. and Young-Pearse, T. L. (2014). The familial alzheimer’s disease APPV717I mutation alters APP processing and tau expression in iPSC-derived neurons. Human Molecular Genetics, 23(13), 3523–3536. https: //doi.org/10.1093/hmg/ddu064

[29]. Iovino, M., Agathou, S., González-Rueda, A., Del Castillo Velasco-Herrera, M., Borroni, B., Alberici, A. and Spillantini, M. G. (2015). Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations. Brain, 138(11), 3345–3359. https: //doi.org/10.1093/brain/awv222

[30]. Pomeshchik, Y., Klementieva, O., Gil, J., Martinsson, I., Hansen, M. G., de Vries, T. and Roybon, L. (2020). Human iPSC-derived hippocampal spheroids: an innovative tool for stratifying alzheimer disease patient-specific cellular phenotypes and developing therapies. Stem Cell Reports, 15(1), 256–273. https: //doi.org/10.1016/j.stemcr.2020.06.001

[31]. Xu, X., Lei, Y., Luo, J., Wang, J., Zhang, S., Yang, X.-J. and Zhong, Z. (2013). Prevention of β-amyloid induced toxicity in human iPS cell-derived neurons by inhibition of cyclin-dependent kinases and associated cell cycle events. Stem Cell Research, 10(2), 213–227. https: //doi.org/10.1016/j.scr.2012.11.005

[32]. Kondo, T., Imamura, K., Funayama, M., Tsukita, K., Miyake, M., Ohta, A. and Inoue, H. (2017). iPSC-based compound screening and In vitro trials identify a synergistic anti-amyloid β combination for alzheimer’s disease. Cell Reports, 21(8), 2304–2312. https: //doi.org/10.1016/j.celrep.2017.10.109

[33]. Cha, M., Kwon, Y., Ahn, H., Jeong, H., Lee, Y. Y., Moon, M. and Mook‐Jung, I. (2017). Protein‐induced pluripotent stem cells ameliorate cognitive dysfunction and reduce aβ deposition in a mouse model of alzheimer’s disease. Stem Cells Translational Medicine, 6(1), 293–305. https: //doi.org/10.5966/sctm.2016-0081

[34]. Shahmoradian, S. H., Lewis, A. J., Genoud, C., Hench, J., Moors, T. E., Navarro, P. P. and Lauer, M. E. (2019). Lewy pathology in parkinson’s disease consists of crowded organelles and lipid membranes. Nature Neuroscience, 22(7), 1099–1109. https: //doi.org/10.1038/s41593-019-0423-2

[35]. Song, X.-Y., Fan, C.-X., Atta-ur-Rahman FRS, Choudhary, M. I. and Wang, X.-P. (2024). Neuro-regeneration or repair: cell therapy of neurological disorders as a way forward. Current Neuropharmacology, 22(14), 2272–2283. https: //doi.org/10.2174/1570159X22666240509092903

[36]. Benabid, A. L., Chabardes, S., Mitrofanis, J. and Pollak, P. (2009). Deep brain stimulation of the subthalamic nucleus for the treatment of parkinson’s disease. Lancet Neurology, 8(1), 67–81. https: //doi.org/10.1016/S1474-4422(08)70291-6

[37]. Martínez-Fernández, R., Rodríguez-Rojas, R., Álamo, M. del, Hernández-Fernández, F., Pineda-Pardo, J. A., Dileone, M. and Obeso, J. A. (2018). Focused ultrasound subthalamotomy in patients with asymmetric parkinson’s disease: a pilot study. Lancet Neurology, 17(1), 54–63. https: //doi.org/10.1016/S1474-4422(17)30403-9

[38]. Seppi, K., Ray Chaudhuri, K., Coelho, M., Fox, S. H., Katzenschlager, R. and Perez Lloret, S. (2019). Update on treatments for nonmotor symptoms of parkinson’s disease—an evidence-based medicine review. Movement Disorders, 34(2), 180–198. https: //doi.org/10.1002/mds.27602

[39]. Prodoehl, J., Rafferty, M., David, F. J., Poon, C., Vaillancourt, D. E., Comella, C. L. and Robichaud, J. A. (2015). Two-year exercise program improves physical function in parkinson’s disease: the PRET-PD study. Neurorehabilitation and Neural Repair, 29(2), 112–122. https: //doi.org/10.1177/1545968314539732

[40]. Devine, M. J., Ryten, M., Vodicka, P., Thomson, A. J., Burdon, T., Houlden, H. and Kunath, T. (2011). Parkinson’s disease induced pluripotent stem cells with triplication of the α-synuclein locus. Nature Communications, 2(1), 440. https: //doi.org/10.1038/ncomms1453

[41]. Byers, B., Cord, B., Nguyen, H. N., Schüle, B., Fenno, L., Lee, P. C. and Palmer, T. D. (2011). SNCA triplication parkinson’s patient’s iPSC-derived DA neurons accumulate α-synuclein and are susceptible to oxidative stress. PLOS One, 6(11), e26159. https: //doi.org/10.1371/journal.pone.0026159

[42]. Soldner, F., Laganière, J., Cheng, A. W., Hockemeyer, D., Gao, Q., Alagappan, R. and Jaenisch, R. (2011). Generation of isogenic pluripotent stem cells differing exclusively at two early onset parkinson point mutations. Cell, 146(2), 318–331. https: //doi.org/10.1016/j.cell.2011.06.019

[43]. Nguyen, H. N., Byers, B., Cord, B., Shcheglovitov, A., Byrne, J., Gujar, P. and Pera, R. R. (2011). LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell, 8(3), 267–280. https: //doi.org/10.1016/j.stem.2011.01.013

[44]. Mohamed, N.-V., Sirois, J., Ramamurthy, J., Mathur, M., Lépine, P., Deneault, E. and Durcan, T. M. (n.d.). Midbrain organoids with an SNCA gene triplication model key features of synucleinopathy. Retrieved from https: //dx.doi.org/10.1093/braincomms/fcab223

[45]. Ryan, S. D., Dolatabadi, N., Chan, S. F., Zhang, X., Akhtar, M. W., Parker, J. and Lipton, S. A. (2013). Isogenic human iPSC parkinson’s model shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription. Cell, 155(6), 1351–1364. https: //doi.org/10.1016/j.cell.2013.11.009

[46]. Heman-Ackah, S. M., Manzano, R., Hoozemans, J. J., Scheper, W., Flynn, R., Haerty, W. and Wood, M. J. (2017). Alpha-synuclein induces the unfolded protein response in parkinson’s disease SNCA triplication iPSC-derived neurons. Human Molecular Genetics, 26(22), 4441–4450. https: //doi.org/10.1093/hmg/ddx331

[47]. Zambon, F., Cherubini, M., Fernandes, H. J. R., Lang, C., Ryan, B. J., Volpato, V. and Wade-Martins, R. (2019). Cellular α-synuclein pathology is associated with bioenergetic dysfunction in parkinson’s iPSC-derived dopamine neurons. Human Molecular Genetics, 28(12), 2001–2013. https: //doi.org/10.1093/hmg/ddz038

[48]. Bono, F., Mutti, V., Devoto, P., Bolognin, S., Schwamborn, J. C., Missale, C. and Fiorentini, C. (2021). Impaired dopamine D3 and nicotinic acetylcholine receptor membrane localization in iPSCs-derived dopaminergic neurons from two parkinson’s disease patients carrying the LRRK2 G2019S mutation. Neurobiology of Aging, 99, 65–78. https: //doi.org/10.1016/j.neurobiolaging.2020.12.001

[49]. Eldeeb, M. A., Bayne, A. N., Fallahi, A., Goiran, T., MacDougall, E. J., Soumbasis, A. and Fon, E. A. (2024). Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress. Proceedings of the National Academy of Sciences, 121(10), e2313540121. https: //doi.org/10.1073/pnas.2313540121

[50]. Jiang, H., Ren, Y., Yuen, E. Y., Zhong, P., Ghaedi, M., Hu, Z. and Feng, J. (2012). Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nature Communications, 3(1), 668. https: //doi.org/10.1038/ncomms1669

[51]. Rosety, I., Zagare, A., Saraiva, C., Nickels, S., Antony, P., Almeida, C. and Schwamborn, J. C. (2023). Impaired neuron differentiation in GBA-associated parkinson’s disease is linked to cell cycle defects in organoids. npj Parkinson’s Disease, 9(1), 166. https: //doi.org/10.1038/s41531-023-00616-8

[52]. Bono, K., Hara-Miyauchi, C., Sumi, S., Oka, H., Iguchi, Y. and Okano, H. J. (2020). Endosomal dysfunction in iPSC-derived neural cells from parkinson’s disease patients with VPS35 D620N. Molecular Brain, 13(1), 137. https: //doi.org/10.1186/s13041-020-00675-5

[53]. Hills, R., Mossman, J. A., Bratt-Leal, A. M., Tran, H., Williams, R. M., Stouffer, D. G. and Lelos, M. J. (2023). Neurite outgrowth and gene expression profile correlate with efficacy of human induced pluripotent stem cell-derived dopamine neuron grafts. Stem Cells and Development, 32(13–14), 387–397. https: //doi.org/10.1089/scd.2023.0043

[54]. Jeon, J., Cha, Y., Hong, Y. J., Lee, I.-H., Jang, H., Ko, S. and Kim, K.-S. (2025). Pre-clinical safety and efficacy of human induced pluripotent stem cell-derived products for autologous cell therapy in parkinson’s disease. Cell Stem Cell, 32(3), 343-360.e7. https: //doi.org/10.1016/j.stem.2025.01.006

[55]. Hu, X., Xu, W., Ren, Y., Wang, Z., He, X., Huang, R. and Cheng, L. (2023). Spinal cord injury: molecular mechanisms and therapeutic interventions. Signal Transduction and Targeted Therapy, 8, 245. https: //doi.org/10.1038/s41392-023-01477-6

[56]. Kajikawa, K., Imaizumi, K., Shinozaki, M., Shibata, S., Shindo, T., Kitagawa, T. and Okano, H. (2020). Cell therapy for spinal cord injury by using human iPSC-derived region-specific neural progenitor cells. Molecular Brain, 13, 120. https: //doi.org/10.1186/s13041-020-00662-w

[57]. Gao, H., Guo, Y., Biswas, S., Li, J., Zhang, H., Chen, Z. and Deng, W. (2022). Promoting oligodendrocyte differentiation from human induced pluripotent stem cells by activating endocannabinoid signaling for treating spinal cord injury. Stem Cell Reviews and Reports, 18(8), 3033–3049. https: //doi.org/10.1007/s12015-022-10405-0

[58]. Zheng, Y., Gallegos, C. M., Xue, H., Li, S., Kim, D. H., Zhou, H. and Cao, Q. (2022). Transplantation of human induced pluripotent stem cell-derived neural progenitor cells promotes forelimb functional recovery after cervical spinal cord injury. Cells, 11(17), 2765. https: //doi.org/10.3390/cells11172765

[59]. Shibata, T., Tashiro, S., Shibata, S., Shinozaki, M., Shindo, T., Hashimoto, S. and Nagoshi, N. (2023). Rehabilitative training enhances therapeutic effect of human iPSC-derived neural stem/progenitor cells transplantation in chronic spinal cord injury. Stem Cells Translational Medicine, 12(2), 83–96. https: //doi.org/10.1093/stcltm/szac089

[60]. Kim, J.-W., Kim, J., Lee, S. M., Rim, Y. A., Sung, Y. C., Nam, Y. and Ju, J. H. (2024). Combination of induced pluripotent stem cell-derived motor neuron progenitor cells with irradiated brain-derived neurotrophic factor over-expressing engineered mesenchymal stem cells enhanced restoration of axonal regeneration in a chronic spinal cord injury rat model. Stem Cell Research & Therapy, 15, 173. https: //doi.org/10.1186/s13287-024-03770-9

[61]. Li, M., Qi, B., Li, Q., Zheng, T., Wang, Y., Liu, B. and Chen, Z. (2024). Human induced pluripotent stem cell/embryonic stem cell-derived pyramidal neuronal precursors show safety and efficacy in a rat spinal cord injury model. Cellular and Molecular Life Sciences: CMLS, 81(1), 318. https: //doi.org/10.1007/s00018-024-05350-9

[62]. Wu, Z., Zhou, Y., Hou, X., Liu, W., Yin, W., Wang, L. and Jiang, X. (2024). Construction of functional neural network tissue combining CBD-NT3-modified linear-ordered collagen scaffold and TrkC-modified iPSC-derived neural stem cells for spinal cord injury repair. Bioactive Materials, 35, 242–258. https: //doi.org/10.1016/j.bioactmat.2024.01.012

[63]. Rahimi Darehbagh, R., Seyedoshohadaei, S. A., Ramezani, R., & Rezaei, N. (2024). Stem cell therapies for neurological disorders: current progress, challenges, and future perspectives. European Journal of Medical Research, 29, 386. https: //doi.org/10.1186/s40001-024-01987-1

Cite this article

Tan,J. (2025). Advances in the Application of Pluripotent Stem Cells in the Research and Treatment of Neurological Diseases. Theoretical and Natural Science,137,92-101.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

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References

[3]. Khawli, L. A. and Prabhu, S. (2013). Drug delivery across the blood–brain barrier. Molecular Pharmaceutics, 10(5), 1471–1472. https: //doi.org/10.1021/mp400170b

[18]. Zu, H. and Gao, D. (2021). Non-viral vectors in gene therapy: recent development, challenges, and prospects. AAPS Journal, 23(4), 78. https: //doi.org/10.1208/s12248-021-00608-7