Disease model studies of developmental and degenerative disorders using brain organoids
Disease | Cell | Dedifferentiation/ gene editing/ disease induction |
Organoid type | Phenotype | Reference |
---|---|---|---|---|---|
Microcephaly (MCPH) |
Patient-derived fibroblasts | Dedifferentiation using lentiviral OSKM | Whole-brain organoid | Small organoid size Immature neural differentiation |
Lancaster et al., 2013 (31) |
Patient-derived fibroblasts | Dedifferentiation using retroviral OSKM | Cerebral cortex organoid | Incomplete neuroepithelial structure Small organoid size Reduced vRG and oRG cell count Immature neurons |
Li et al., 2017 (47) | |
Embryonic stem cells | ZIKA virus infection | Whole-brain organoid | Increased apoptosis Reduced stem cell self-renewal Collapse of the neuroepithelium |
Cugola et al., 2016 (50) | |
Pluripotent stem cells | ZIKA virus infection | Cerebral cortex organoid | Small organoid size Increased apoptosis |
Qian et al., 2016 (51) | |
Autism spectrum disorder (ASD) | Patient-derived fibroblasts | Dedifferentiation using retroviral OSKM | Forebrain organoid | Increased FOXG1 expression Increased GABAergic inhibitory neurons |
Mariani et al., 2015 (52) |
Patient-derived fibroblasts | CHD9 knockout by gene editing | Whole-brain organoid | Abnormal DLX expression Increased GABAergic inhibitory neurons |
Wang et al., 2017 (53) | |
CNTNAP2- knockout mouse fibroblasts | Dedifferentiation using retroviral OSKM | Whole-brain organoid | Increased GABAergic inhibitory neurons | Hali et al., 2020 (54) | |
Rett’s syndrome (RTT) |
Patient-derived fibroblasts | Dedifferentiation using retroviral OSKM | Whole-brain organoid | Abnormal miR-199 and miR0214 expression Abnormal migration of neural progenitor cells |
Mellios et al., 2018 (55) |
Embryonic stem cells | MECP2 gene knockout and insertion | Cerebral cortex organoid, medial ganglionic eminence organoid | Deformity and dysfunction of GABAergic inhibitory neurons | Xiang et al., 2020 (56) | |
Patient-derived fibroblasts | Dedifferentiation using retroviral OSKM | Dorsal forebrain - ventral forebrain assembloid | Abnormal tangential migration of interneurons | Gomes et al., 2020 (57) | |
Timothy syndrome (TS) | Patient-derived fibroblasts | Dedifferentiation using retroviral OSKM | Cerebral cortex - corpus striatum assembloid | Abnormal tangential migration of interneurons | Birey et al., 2017 (74) |
Down syndrome (DS) |
Patient-derived fibroblasts | Sendai virus-based OSKM | Forebrain organoid | Overproduction of OLIG2-positive progenitors Overproduction of GABAergic inhibitory neurons |
Xu et al., 2019 (58) |
Patient-derived fibroblasts | Sendai virus-based OSKM | Whole-brain organoid | Small organoid size Abnormal DSCAM/PAK1 signaling Decreased neurogenesis |
Tang et al., 2021 (59) | |
Alzheimer’s disease (AD) | Pluripotent stem cells | PSEN2 mutation correction through gene editing | Whole-brain organoid | Small organoid size High Aβ42/Aβ40 ratio Abnormal Ca2+ homeostasis Excessive neuron activation |
Yin and VanDongen, 2021 (62) |
Patient-derived fibroblasts | Dedifferentiation using an episomal vector | Whole-brain organoid | Increased apoptosis Synaptic dysfunction Increased amyloid beta Increased phosphorylated tau |
Zhao et al., 2020 (63) | |
Pluripotent stem cells | PITRM1 gene knockout through gene editing | Whole-brain organoid | Synaptic dysfunction Amyloid beta aggregation Tau plaque formation |
Pérez et al., 2021 (64) | |
Parkinson’s disease (PD) | Patient-derived fibroblasts | Dedifferentiation using a lentiviral OSKM | Midbrain organoid | Increased sensitivity to toxicity Increased alpha synuclein Increased thioflavin T-positive cells |
Kim et al., 2019 (66) |
Embryonic stem cells | GBA1 knockout and SNCA overexpression through gene editing | Midbrain organoid | Accumulation of Lew bodies | Jo et al., 2021 (67) |
vRG: ventricular radial glia, oRG: outer radial glia.