Current Development of iPSC-Based Modeling in Neurodegenerative Diseases
Abstract
1. Introduction
2. Generation of iPSCs
2.1. Delivery Methods
2.2. Reprogramming Factors
2.3. Somatic Cell Sources
3. Neural Differentiation of iPSCs
3.1. Neural Stem Cells
3.2. Neurons
3.3. Astrocytes
3.4. Microglia
3.5. Oligodendrocytes
3.6. Brain Organoids
3.7. Assembloids
4. Neurodegenerative Disease Modeling with Patient-Derived iPSCs
4.1. Alzheimer’s Disease
4.2. Parkinson’s Disease
4.3. Huntington’s Disease
4.4. Rare Neurodegenerative Diseases
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Methods | Advantages | Disadvantages | References |
---|---|---|---|
Retroviral and lentiviral vectors | Highly efficient and robust | Risk of transgene reactivation | [12] |
Adenoviral vectors | Lower risk of transgene reactivation | Low reprogramming efficiency; unsuitable for clinical use | [11,13] |
Sendai virus | Higher efficiency; RNA virus can be completely removed | Still involves challenges in clinical application | [11,13] |
PiggyBac | Lower risk of genomic instability and mutations | Low reprogramming efficiency; limited cell sources | [14,15,16] |
Minicircle vectors | Lower risk of genomic instability and mutations | Low reprogramming efficiency; limited cell sources | [14,15,16] |
Episomal plasmids | No genomic integration risk; cost-effective and easy to use | Requires daily transfection; moderate efficiency | [17,18] |
RNA Delivery | Lower mutagenic risk; high efficiency | Limited to specific cell types (e.g., fibroblasts, peripheral blood cells) | [19,20,21] |
Factors | Functions | References | |
---|---|---|---|
Yamanaka factors | OCT3/4, SOX2, KLF4, c-MYC | OCT3/4, SOX2, and KLF4 maintain pluripotency and inhibit differentiation c-MYC enhances reprogramming efficiency and promotes cell proliferation | [23] |
Alternative factor combinations | OCT3/4, SOX2, NANOG, LIN28 | NANOG maintains self-renewal of stem cells LIN28 regulates RNA modification and expression | [24] |
Enhancement or complementary factors | GLIS1, NR5A2, SALL4 | Substitute for c-MYC or OCT3/4 to improve reprogramming efficiency and stabilize cell states | [25,26,27] |
Chemical cocktails | (1) CHALP cocktail: CHIR99021, PD0325901, LIF, A-83-01, bFGF, HA-100 | Enhances reprogramming efficiency | [2,28] |
(2) Alternative chemical cocktail: cyclic pifithrin-α, A-83-01, CHIR99021, thiazovivin, NaB, PD0325901 | Significantly enhances reprogramming efficiency, particularly in hUCs | [2,29] | |
Epigenetic modulators | DNA methyltransferase inhibitors, histone deacetylase inhibitors | Regulate DNA methylation, histone acetylation, and the expression of pluripotency-associated genes to enhance reprogramming efficiency | [30,31,32] |
Cell Type | Sources | Advantages |
---|---|---|
Fibroblasts | Skin | Readily accessible and widely used |
PBMCs | Blood | Non-invasive; useful for clinical applications |
Keratinocytes | Skin or hair | Non-invasive and readily accessible |
MSCs | Bone marrow, adipose tissue, teeth | Abundant and frequently used in regenerative research |
Renal epithelial cells | Urine | Highly convenient and non-invasive |
NSCs and NPCs | Brain tissue | Inherent pluripotency; useful for neurological applications |
Liver cells | Liver tissue | Expands potential applications |
Stomach cells | Stomach tissue | Expands potential applications |
Cord blood cells | Cord blood | Readily available from umbilical cord; useful in neonatal research |
Differentiated Cell/Organoid Type | Differentiation Methods | Limitations | References |
---|---|---|---|
NSCs/NPCs |
| Requires intermediate steps; limited differentiation efficiency | [3,56,57] |
Neurons (e.g., dopaminergic, GABAergic, glutamatergic) |
| Complex protocols; variability in differentiation outcomes; phenotypic instability with direct conversion | [3,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74] |
Astrocytes |
| Significant plasticity; variability across protocols; in vitro astrocytes may not fully replicate in vivo properties | [72,75,76,77,78,79,80,81,82,83,84] |
Microglia |
| High technical complexity; multiple steps; phenotypic and functional differences from in vivo counterparts | [85,86,87,88,89,90,91,92] |
Oligodendrocytes |
| Time-consuming; phenotypic instability with direct transcription factor induction; challenges in achieving purity | [93,94,95,96,97,98,99,100,101,102,103] |
Brain organoids (e.g., cortical, hippocampal, midbrain, cerebellar) | Non-guided (intrinsic morphogenetic potential or guided (dual SMAD inhibition, region-specific factors such as SHH, RA, WNT inhibitors) | Lack of vascularization and heterogeneity; difficulty in precisely controlling differentiation and region specificity | [104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125] |
iPSC-Derived Model | AD’s Pathological Features | References |
---|---|---|
Neurons |
| [128,131,132,133,134,135,136,137,138,139,140] |
NSCs/NPCs |
| [131,141,142] |
Microglia |
| [85,143,144] |
Astrocytes |
| [145,146,147,148] |
Oligodendrocytes |
| [149] |
3D brain organoids |
| [150,151,152,153,154,155] |
iPSC-Derived Model | PD’s Pathological Features | References |
---|---|---|
DA neurons |
| [2,5,105,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188] |
Astrocytes |
| [189,190,191] |
Microglia |
| [191,192,193] |
Neural stem cells |
| [194,195] |
3D brain organoids |
| [104,196,197] |
iPSC-Derived Model | HD’s Pathological Features | References |
---|---|---|
Neural progenitor/stem cells (NPCs/NSCs) |
| [206,207,208] |
Forebrain neurons |
| [206] |
Striatal-like GABAergic neurons (MSNs) |
| [209,210,211] |
Astrocytes |
| [207,208] |
Glial cells (general) |
| [208] |
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Guo, X.; Wang, X.; Wang, J.; Ma, M.; Ren, Q. Current Development of iPSC-Based Modeling in Neurodegenerative Diseases. Int. J. Mol. Sci. 2025, 26, 3774. https://doi.org/10.3390/ijms26083774
Guo X, Wang X, Wang J, Ma M, Ren Q. Current Development of iPSC-Based Modeling in Neurodegenerative Diseases. International Journal of Molecular Sciences. 2025; 26(8):3774. https://doi.org/10.3390/ijms26083774
Chicago/Turabian StyleGuo, Xiangge, Xumeng Wang, Jiaxuan Wang, Min Ma, and Qian Ren. 2025. "Current Development of iPSC-Based Modeling in Neurodegenerative Diseases" International Journal of Molecular Sciences 26, no. 8: 3774. https://doi.org/10.3390/ijms26083774
APA StyleGuo, X., Wang, X., Wang, J., Ma, M., & Ren, Q. (2025). Current Development of iPSC-Based Modeling in Neurodegenerative Diseases. International Journal of Molecular Sciences, 26(8), 3774. https://doi.org/10.3390/ijms26083774