Table 2 hPSC-derived brain organoids for modelling neural disorders and cancer
Disease | Genes/Cell types | Brain region/Organoid type | Observed phenotypes in organoids | Conclusions | Reference |
|---|---|---|---|---|---|
Microcephaly | CDK5RAP2/ Patient iPSC | Whole brain/cereal organoid | Patient organoids showed a smaller overall size and a reduction of the progenitor zones | CDK5RAP2 mutation in brain organoids leads to decreased NPCs proliferation and premature NPCs differentiation | [11] |
CPAP/ Patient iPSC | Patient organoids exhibited a reduced size, enlarged ventricular lumen, increased number of cilia as well as premature neurogenesis | CPAP mutation causes cilia disassembly, and eventually leads to a delayed cell-cycle re-entry and premature neurogenesis | [51] | ||
WDR62/Genetically modified iPSC | WDR62 depletion resulted in smaller cerebral organoid sizes due to reducing the oRGs proliferation and inducing the early neurogenesis | WDR62-CEP170-KIF2A pathway functions as a contributor to microcephaly | [59] | ||
NARS1/Patient iPSC | Patient organoids showed reduced proliferation of radial glial cells, resulting in smaller organoids characteristic of microcephaly | NARS1 is required to meet protein synthetic needs and to support RGC proliferation in human brain development | [60] | ||
IER3IP1/Genetically modified iPSC | IER3IP1 KO organoids showed a smaller size, neural rosettes and reduced NPCs compared to WT organoids | The regulation of extracellular matrix protein secretion by IER3IP1 is involved in brain size control and is implicated in microcephaly | [61] | ||
Epilepsy | TSC1/2/Genetically modified iPSC | Whole brain/cereal organoid | Loss of TSC1 or TSC2 in brain organoids prominently disrupted the developmental suppression of mTORC1 pathway and resulted in abnormal differentiation and hypertrophy of human neurons and glia, giving rise to dysplastic cells resembling those found in tubers | mTOR inhibition during a critical developmental period prevents the formation of dysplastic cells | [79] |
CACNA1C/Timothy syndrome patient iPSC | Cortical-subpallium/ Assembloids | Abnormal salutatory migration of interneurons was observed in patient assembloids with TS | Treating the assembloids with L-type calcium channels inhibitors (nimodipine) can rescued the saltatory defects | [37] | |
Autism spectrum disease (ASD) | FOXG1/ASD patient iPSC | Whole brain/cereal organoid | ASD-derived organoids exhibited an accelerated cell cycle and overproduction of GABAergic inhibitory neurons | Overexpression of FOXG1 induced GABAergic neuron fate is a developmental precursor of ASD | [83] |
CDH8/Genetically modified iPSC | Transcriptome analysis using cerebral organoids with CHD8 haplosufficiency revealed a subset of dysregulated genes overlapping those of the idiopathic ASD organoids | CHD8 may be a genetic risk of ASD | [84] | ||
RAB39b/Genetically modified iPSC | Brain organoids carrying the RAB39b gene mutation showed enlarged sizes | RAB39b mutation promotes PI3K-AKT-mTOR activity and alters cortical neurogenesis, leading to ASD-like behaviors | [87] | ||
Alzheimer’s disease (AD) | APP and PSEN1/AD patient iPSC | Whole brain/cereal organoid | AD-associated brain organoids showed increased amyloid aggregation, hyperphosphorylated tau protein, and increased apoptosis | Brain organoids represent an alternative model for studying the pathology of genetic forms of AD | [95] |
APOE4/AD patient iPSC | AD patients carrying APOE4 increased levels of Aβ and phosphorylated tau, and exacerbated neuronal cell apoptosis and synapse loss | APOE4 exacerbates AD pathogenesis in cerebral organoids | [97] | ||
PITRM1/Genetically modified iPSC | PITRM1 knockout organoids showed accumulation of protein aggregates, tau pathology, and neuronal cell death | PITRM1 plays a protective role of in AD pathogenesis | [98] | ||
BACE2/AD patient iPSC | Trisomy of BACE2 skewed non-amyloidogenic Aβ peptide ratios and suppresses AD-like pathology in organoids | BACE2 is an AD suppressor in human brain | [102] | ||
Parkinson’s disease (PD) | LRRK2G2019S /PD patient and genetically modified iPSCs | Midbrain/midbrain organoid | LRRK2G2019S hiPSC-derived midbrain organoids showed reduction of the number and arborisation complexity of TH+ cells, impaired mitochondrial function, and increased apoptosis | LRRK inhibition and knockdown of TXNIP can rescue the observed phenotypes in PD midbrain organoids | |
Huntington’s disease (HD) | HTT/ integration-free HD hiPSC with 21, 28, 33, 60, 109, and 180 CAG repeats | Whole brain/cereal organoid | HD hiPSC-derived organoids showed immature ventricular zone and defects in neuroectoderm and rosette formation | HD-associated phenotypes, including the cortical and striatal specification defects, and neuronal migration and differentiation defects are CAG expansion dependant | [114] |
GBM initiation | MYCOE, NF1−/PTEN−/TP53−, and EGFRvIIIOE/CDKN2A−/PTEN−/genetically modified iPSC | Whole brain/neoCOR | Genetically modified cerebral organoids induced overgrowth and exhibited many features of cancer | neoCOR is an ideal model to study GBM initiation and progression in human brain-like tissues | [122] |
HRasG12V/TP53−/genetically modified iPSC | Genetically modified cerebral organoids induced mesenchymal GBMs and exhibited an invasive phenotype orthotopically xenografted into immunodeficient mice | [123] | |||
GBM invasion | Â | Co-culturing of GBM spheroids with cerebral organoids | Tumor spheroids could spontaneously infiltrate early-stage cerebral organoids and exhibited an invasive phenotype | Co-culture model is an ideal to study GBM/GSCs growth and invasive behaviours in brain-like tissues | [124] |
Co-culturing of GSCs with cerebral organoids: GLICO (GLIoma cerebral organoids) | GSCs home toward the human cerebral organoid and deeply invaded and proliferated within the host tissue | [125] |