TABLE 2.
Summary of the neurogenic defects induced by environmental adversities modeled in brain organoids.
| Group of environmental adversity | Environmental adversity | Publication | Organoid protocol | Regional identity, age of the organoid at the start of experiment | Major findings |
|---|---|---|---|---|---|
| Viral infections with vertical transmission | Zika virus | Gabriel et al. (2017) | Gabriel et al. (2017) | Brain, Day 9 | Infection of NPCs followed by either apoptosis or premature differentiation due to defect in centriole assembly |
| Dang et al. (2016) | Lancaster et al. (2013) | Cerebral, Day 10 | Restricted growth | ||
| TLR3 mediates transcriptional dysregulation of apoptosis and regulators of neurogenesis | |||||
| Qian et al. (2016) | Qian et al. (2016) | Cortical, Day 14 or 80 | Infection in NPCs, including oRGs, as well as in IPCs and immature neurons | ||
| Disrupted proliferation in the VZ-like areas | |||||
| Decreased neuronal output and increased size of ventricle-like cavities | |||||
| Watanabe et al. (2017) | Watanabe et al. (2017) | Cerebral, Day 21 | Restricted growth | ||
| Activation of innate immune response promoting cell death | |||||
| Albanese et al. (2020) | Lancaster et al. (2013) | Cerebral, Day 21 | Restricted growth | ||
| Decreased number of VZ-like areas | |||||
| Reduced number of vRGs accompanied with reduced neuronal output | |||||
| Wells et al. (2016) | Wells et al. (2016) | Cerebral, Day 24 | Knockout of AXL does not protect VZ-like areas from viral infection and apoptosis | ||
| Cugola et al. (2016) | Lancaster et al. (2013) | Cerebral, Day 28 | Disruption of proliferative zones | ||
| Decreased neuronal number and increased apoptosis | |||||
| Garcez et al. (2016) | Lancaster et al. (2013) | Cerebral, Day 35 | Restricted growth | ||
| Yoon et al. (2017) | Qian et al. (2016) | Cortical, Day 45 | Disrupted apical polarity complex in vRGs, disrupted adherens junctions leading to premature differentiation | ||
| Cytomegalovirus | Brown et al. (2019) | Lancaster et al. (2013) with modifications | Cerebral, Day 0 | Decreased cellularity | |
| Regions of necrosis and cysts | |||||
| Disrupted VZ-like areas and radial scaffold | |||||
| Sun et al. (2020) | Lancaster et al. (2013) with modifications | Cerebral, Day 30 | Restricted growth | ||
| Decreased proliferation in the VZ-like areas | |||||
| Increased apoptosis adjacent to the VZ-like areas | |||||
| PDGFRa and EGFR are potential viral entry receptors | |||||
| Infection in TBR2-positive IPCs | |||||
| Decreased neuronal output | |||||
| Upregulated immune response and downregulated metabolism-related gene expression | |||||
| Cosset et al. (2015) | Preynat-Seauve et al. (2009) | Engineered neural tissue, age not reported | Upregulated lipid metabolism and inflammation-related genes | ||
| Infection in doublecortin-positive newborn neurons but not in PAX6-positive NPCs | |||||
| Qiao et al. (2020) | Lancaster et al. (2013) with modifications | Cerebral, Day 15 | Decreased expression of SOX2 and Nestin | ||
| Decreased thickness of CP-like structures and decreased expression of neuronal markers | |||||
| D’Aiuto et al. (2019) | D’Aiuto et al. (2019) | Brain, age not reported | Infection in MAP2-positive neurons with formation of neuronal syncytia | ||
| Rybak-Wolf et al. (2021) | Lancaster et al. (2017) | Cerebral, enriched for dorsal forebrain cellular identities, Day 60 | Infection in different cell types with highest viral load in NPCs | ||
| Cell type-specific changes in transcriptional profile | |||||
| Global elongation of poly(A) tails and preferential use of distal 3’UTR in mRNA molecules | |||||
| SARS-CoV-2 | Ramani et al. (2020) | Gabriel et al. (2016), a modification of Lancaster et al. (2013) | Cerebral, Day 15 or 60 | Little to no infection in organoids inoculated with the virus on Day 15 of differentiation, significant infection in Day 60 organoids | |
| Infection in Tuj1-positive neurons | |||||
| Apoptotic neuronal cell death due to aberrant tau localization | |||||
| Zhang et al. (2020) | Lancaster et al. (2013) | Cerebral, Day 35 | Infection in Nestin-positive NPCs and Tuj1-positive neurons | ||
| Productive infection of the organoid | |||||
| Mesci et al. (2020) | Trujillo et al. (2019) | Cortical, Day 52 | Infection and increased apoptosis rate in Nestin-positive NPCs, MAP2-positive neurons and GFAP-positive astrocytes | ||
| The phenotype is reversed by sofosbuvir | |||||
| Song et al. (2020) | Lancaster et al. (2013) | Cerebral, Week 9 | Productive infection in SOX2-positive NPCs and MAP2-positive neurons but not in GFAP-positive astroglia | ||
| ACE2 protein localization to MAP2-positive neurons and close to the VZ-like cavities | |||||
| Overall increased apoptosis rate within the organoid irrespective of the infection status of the cell | |||||
| Hypermetabolic state of the infected cells and overall downregulation of catabolic processes | |||||
| Andrews et al. (2021) | Pollen et al. (2019) | Cortical, Week 5, 10, 16, or 22 | Infection in double-GFAP,AQP4-positive astrocytes and rare infection of NeuN-positive neurons at Week 22 | ||
| No infection in SOX2-positive NPCs at Week 5 and 10 | |||||
| No ACE2 protein expression detected | |||||
| Jacob et al. (2020) | Qian et al. (2016) | Cortical, age not reported | Infection in doublecortin-positive neurons | ||
| Maternal stress, medication, and substance use | Glucocorticoids (dexamethasone) | Cruceanu et al. (2020) | Lancaster et al. (2013) | Cerebral, Day 45 | Cerebral organoids express the molecular machinery for response to glucocorticoids starting from Day 17 of differentiation |
| GR expression is enriched in NPCs | |||||
| Altered expression profile indicates that dexamethasone interferes with neuronal differentiation | |||||
| Ethanol | Zhu et al. (2017) | Zhu et al. (2017), an organ-on-chip modification of Lancaster et al. (2013) | Cerebral, Day 10 | Apoptosis induction | |
| Decreased SOX2-posivive NPC number | |||||
| Increased Tuj1-posivive neuron number | |||||
| Decreased expression of cell adhesion molecules | |||||
| Arzua et al. (2020) | Lancaster et al. (2013) | Cerebral, Day 60 | Apoptosis induction in NeuN-positive neurons but not in S100B-positive astrocytes | ||
| Altered energy metabolism and mitochondrial function | |||||
| Altered gene expression profile including genes related to neurodevelopment and neurological diseases | |||||
| Nicotine | Wang et al. (2018) | Wang et al. (2018), an organ-on-chip modification of Lancaster et al. (2013) | Cerebral, Day 11 | Induction of apoptosis | |
| Increased proportion of Tuj1-positive neurons indicating premature differentiation | |||||
| Decreased expression of forebrain markers PAX6 and FOXG1 | |||||
| Cannabis | Ao et al. (2020) | Ao et al. (2020), a microfluidic modification of Lancaster et al. (2013) | Cerebral, Day 3 | Increased PAX6-positive NPCs number and increased thickness of VZ-like areas indicating increased proliferation of NPCs | |
| Decreased expression of neuronal markers Tuj1 and CTIP2 | |||||
| Downregulated CB1 expression | |||||
| Cocaine | Lee et al. (2017) | Lee et al. (2017) | Cortical, Day 32 | Decreased PAX6-positive NPCs number | |
| Increased migration of BrdU-positive neurons indicating premature differentiation | |||||
| Increased ROS formation | |||||
| Fetal hypoxia | Fetal hypoxia | Boisvert et al. (2019) | Boisvert et al. (2019) | Brain, Day 10 | Induction of apoptotic program |
| Decreased expression of cortical markers FOXG1, CTIP2, TBR1 | |||||
| Both the induction of apoptotic program and decreased cortical marker expression may be reverted by minocycline | |||||
| Daviaud et al. (2019) | Lancaster et al. (2013) | Cerebral, Day 28 | Immediate cell death in VZ-like areas and increased CTIP2-positive neuron number | ||
| Delayed decrease in TBR2-positive IPCs and FAM107A-positive oRGs | |||||
| Self-renewal divisions in aRGs at the expense of indirect neurogenesis | |||||
| Paşca et al. (2019) | Sloan et al. (2018) | Cortical spheroid, Day 75 | No cell death observed | ||
| PAX6-positive NPCs number not altered | |||||
| Decreased number of TBR2-positive IPCs due to premature cell cycle exit and differentiation |