Patient-Derived Induced Pluripotent Stem Cells (iPSCs) and Cerebral Organoids for Drug Screening and Development in Autism Spectrum Disorder: Opportunities and Challenges
Abstract
:1. Introduction
2. iPSC Models of ASDs
2.1. iPSCs-Derived Neural Progenitor Cells
2.2. iPSCs-Derived Neurons
2.3. iPSCs-Derived Astrocytes
2.4. iPSCs-Derived Oligodendrocytes
2.5. Current Challenges for the Applicability of iPSCs in ASD Modeling
3. Brain Organoid Models of ASDs
Current Challenges for the Applicability of Brain Organoids in ASD Modeling
4. Use of ASD Models for Drug Discovery and Development
5. Conclusions and Future Directions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cell Types | Advantages | Disadvantages |
---|---|---|
ESCs | Low cost Established protocols for maintenance in culture Any cell type differentiation (pluripotency) Efficient differentiation | Mutation rate Embryo destruction Ethical/political concerns Difficulty to obtain Lack of genetic/immunohistocompatibility match |
MSCs | Availability Ease to isolate and expand No ethical concerns Trans-differentiation capacities Success in various clinical applications | Limited number of cell type differentiation (multipotency) Loss of proliferative and differentiation capacities over continuous passages Standardization difficulty Genetic heterogeneity |
iPSCs | No ethical concerns Ease to obtain Use of abundant somatic cells of donor Any cell type differentiation (pluripotency) Genetic/immunohistocompatibility match Utility for drug development and developmental studies | Cost of production Difficulty of standardization, reproducibility and maintenance Tumorigenesis Genomic instability |
Disease | Genetic Mutations in Samples (n) | iPSCs-Based Models | Relevant Findings | Effective Drugs | Reference |
---|---|---|---|---|---|
Non-syndromic ASD | different no ASD-related variants (3) | neurons and astrocytes | decreased synapses and release of excitatory neurotransmitters, glial dysfunction, and high levels of IL-6 | anti-IL-6 | [31] |
different no ASD-related variants (8) | NPCs and neurons | increased proliferation in NPCs, abnormal neurogenesis, reduced synaptogenesis, and decreased release of inhibitory/excitatory neurotransmitters | IGF-1 | [35] | |
different no ASD-related variants (3) | NPCs | hyperproliferation of NPCs | [36] | ||
rare compound heterozygous missense variants in RELN (1) | NPCs | impaired crosstalk between mTORC1 and Reelin-DAB1 pathways | rapamycin | [37] | |
de novo balanced translocation in TRPC6 (1) | NPCs and neurons | abnormal neuronal development and morphology, fewer dendritic spines and synapses | IGF-1 and hyperforin | [38] | |
loss-of-function mutations in FOXG1 (4) | neurons and brain organoids | overproduction of GABAergic neurons and GABA neurotransmitter | [69] | ||
heterozygous loss-of-function mutations in SHANK2 (2) | neurons | increased dendrite length and complexity, synapse number, and frequency of spontaneous excitatory post-synaptic currents | agonist of mGluRs DHPG | [70] | |
different no ASD-related variants (8) | brain organoids | neurodevelopmental abnormalities triggered by temporal dysregulation of specific gene networks | [121] | ||
heterozygous knockout of CHD8 (1) | brain organoids | enrichment of genes involved in GABAergic interneuron development and Wnt/β-catenin signaling | [122] | ||
RTT | missense, frameshift and nonsense mutations in MECP2 (4) | NPCs and neurons | reduced soma size, dendritic spine densities and synapses, altered Ca2+ signaling, and electrophysiological defects | IGF-1 and gentamicin | [39] |
frameshift mutation in MECP2 (1) | NPCs and neurons | increased frequency of de novo LINE-1 retrotransposition | [40] | ||
different duplications in MECP2 (3) | NPCs and neurons | altered expression of neuronal progenitor genes, increased synaptogenesis and dendritic complexity with altered network synchronization | histone deacetylase inhibitor NCH-51 | [41] | |
large deletion in MECP2 (1) | NPCs and cortical neurons | repressed translation and decreased ribosome engagement of NEDD4-family ubiquitin ligases | [42] | ||
missense mutations in MECP2 (2) | neurons | impaired microtubule network and decreased acetylated α-tubulin | selective inhibitors of HDAC6 | [71] | |
missense and nonsense mutations in MECP2 (3) | neurons and astrocytes | neuronal morphological abnormalities mediated by mutant astrocytes | IGF-1 and GPE | [105] | |
missense and nonsense mutations in MECP2 (2) | astrocytes | perturbed astrocyte differentiation | [106] | ||
missense and frameshift mutations in MECP2 (2) | brain organoids | impaired neurogenesis, neuronal differentiation and migration | [123] | ||
missense and nonsense mutations in MECP2 (3) | brain organoids | cell-type-specific impairments | BET inhibitor JQ1 | [124] | |
CDKL5 disorder | missense and nonsense mutations in CDKL5 (2) | neurons | decreased density of dendritic spines and reduced number of excitatory synapse | [72] | |
translocation t(7;X) inactivating CDKL5 (1) | neurons | decreased density of dendritic spines and loss of synaptic contacts | [75] | ||
FXS | >200 CGG repeats in 5′UTR FMR1 (3) | NPCs | abnormal expression of key NPC genes (SOX1, NOTCH1, PAX6) | [43] | |
>200 CGG repeats in 5′UTR FMR1 (4) | NPCs | impaired Ca2+ signaling affecting neuronal differentiation | [44] | ||
>700 CGG repeats in 5′UTR FMR1 (3) | neurons | impaired neuronal differentiation and maturation | [76] | ||
FMR1 knockout (2) | neurons | abnormal synaptic transmission, neuronal differentiation, and cell proliferation | [80] | ||
>700 CGG repeats in 5′UTR FMR1 (3) | neurons | altered neurite outgrowth and branching defects | [81] | ||
94 CGG repeats in 5′UTR FMR1 (1) | neurons | dysregulated Ca2+ signals, reduced synaptic protein expression, and shorter neurites | [82] | ||
TSC | de novo mutations in TSC2 (2) | NPCs and neurons | delayed neuronal differentiation | [45] | |
nonsense mutation in TSC1 (1) | NPCs | enhanced proliferation, aberrant neurite outgrowth, and enlarged cell size | rapamycin | [46] | |
splicing mutation in TSC1 (1) | neurons | enlarged soma, decreased neurite length, and abnormal connections | [83] | ||
de novo mutation in TSC1 and frameshift mutation in TSC2 (2) | co-cultures of cortical neurons and oligodendrocytes | cellular hypertrophy and increased axonal density | rapamycin | [84] | |
single or biallelic mutations in TSC2 (2) | neurons | morphological changes | rapamycin | [86] | |
loss-of-function mutations in TSC1 and TSC2 (2) | brain organoids | impaired developmental suppression of mTORC1 signaling by loss of either TSC1 or TSC2 | rapamycin | [125] | |
PMDS | small/large 22q13.3 deletions and frameshift mutation in SHANK3 (7) | NPCs | disrupted neurogenesis leading to altered excitatory/inhibitory balance | [47] | |
22q13 deletion (2) | neurons | impaired excitatory synaptic transmission | IGF-1 | [87] | |
de novo truncating and frameshift mutations in SHANK3 (2) | neurons | impaired excitatory synaptic transmission | lithium and valproic acid | [88] | |
de novo truncating mutations in SHANK3 (4) | pyramidal neurons | decreased dendritic spines and altered spinogenesis | [89] | ||
heterozygous and homozygous SHANK3 deletions (2) | neurons | decreased neurite outgrowth, hyperexcitability, increased input resistance, and disrupted excitatory synaptic transmission | [90] | ||
TS | G406R missense mutation in CACNA1C (5) | NPCs and neurons | dysregulated Ca2+ signaling, impaired neuronal differentiation, increased TH and catecholamine expression | roscovitine | [48] |
G406R missense mutation in CACNA1C (3) | NPCs | dysregulated Ca2+ signaling affecting neuronal development and function | [49] | ||
G406R missense mutation in CACNA1C (2) | neurons | Ca2+-dependent dendritic retraction and altered cellular structure | C3 transferase | [91] | |
G406R missense mutation in CACNA1C (3) | neurons | altered differentiation in the developing cortex | [92] | ||
G406R missense mutation in CACNA1C (3) | brain organoids | delayed migration of inhibitory neurons | nimodipine | [127] | |
AS | maternal 15q11-q13 deletion including UBE3A (2) | neurons | no phenotypic alterations | [93] | |
3bp deletion in the maternally inherited UBE3A (1) | neurons | late paternal UBE3A silencing during neuronal differentiation | [96] | ||
large 15q11–q13 deletion (3) | neurons | reduced synaptic activity and plasticity | [97] | ||
15q11.2-q13 microdeletion including UBE3A (1) | brain organoids | neuronal hyperexcitability | BK channels antagonist | [128] | |
PWS | paternal 15q11-13 deletion (1) | neurons | no phenotypic alterations | [93] |
Limitations of iPSCs | Potential Solutions/Approaches |
---|---|
Limited amount of patient-derived cell lines | Generation of biobanks of cells derived from patients and unaffected individuals |
Lack of proper ASD control | Use of TALEN and CRISPR/Cas9 genome-editing techniques to create isogenic cell lines |
Line-to-line variability | Use of TALEN and CRISPR/Cas9 genome-editing techniques to create isogenic cell lines More defined differentiation procedures for both 2D and 3D cultures |
Lack of organoid-to-organoid reproducibility | Use of 3D bioprinting models |
Lack of vascularization | In Vivo transplantation in animal models Use of combined progenitors (neural and mesenchymal stem cells) Promotion of blood vessel formation by VEGF supplementation in brain organoids |
Limited long-term maturation of brain organoids | Optimization of growth conditions by spinning bioreactors In vivo transplantation in animal models |
High cost of culturing organoids | Miniaturized bioreactors with reduced incubator space and decreased volume of media |
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Villa, C.; Combi, R.; Conconi, D.; Lavitrano, M. Patient-Derived Induced Pluripotent Stem Cells (iPSCs) and Cerebral Organoids for Drug Screening and Development in Autism Spectrum Disorder: Opportunities and Challenges. Pharmaceutics 2021, 13, 280. https://doi.org/10.3390/pharmaceutics13020280
Villa C, Combi R, Conconi D, Lavitrano M. Patient-Derived Induced Pluripotent Stem Cells (iPSCs) and Cerebral Organoids for Drug Screening and Development in Autism Spectrum Disorder: Opportunities and Challenges. Pharmaceutics. 2021; 13(2):280. https://doi.org/10.3390/pharmaceutics13020280
Chicago/Turabian StyleVilla, Chiara, Romina Combi, Donatella Conconi, and Marialuisa Lavitrano. 2021. "Patient-Derived Induced Pluripotent Stem Cells (iPSCs) and Cerebral Organoids for Drug Screening and Development in Autism Spectrum Disorder: Opportunities and Challenges" Pharmaceutics 13, no. 2: 280. https://doi.org/10.3390/pharmaceutics13020280