TY - JOUR
KW - Assembloid
KW - Autism
KW - brain organoid
KW - Dominant
KW - epilepsy
KW - Gene-environment-interaction
KW - Genotype-phenotype
KW - Microcephaly
KW - Mosaic
KW - Mutation
KW - Neural rosette
KW - Recessive
AU - Lu Wang
AU - Charlotte Owusu-Hammond
AU - David Sievert
AU - Joseph G. Gleeson
AB - The past decade has seen an explosion in the identification of genetic causes of neurodevelopmental disorders, including Mendelian, de novo, and somatic factors. These discoveries provide opportunities to understand cellular and molecular mechanisms as well as potential gene-gene and gene-environment interactions to support novel therapies. Stem cell–based models, particularly human brain organoids, can capture disease-associated alleles in the context of the human genome, engineered to mirror disease-relevant aspects of cellular complexity and developmental timing. These models have brought key insights into neurodevelopmental disorders as diverse as microcephaly, autism, and focal epilepsy. However, intrinsic organoid-to-organoid variability, low levels of certain brain-resident cell types, and long culture times required to reach maturity can impede progress. Several recent advances incorporate specific morphogen gradients, mixtures of diverse brain cell types, and organoid engraftment into animal models. Together with nonhuman primate organoid comparisons, mechanisms of human neurodevelopmental disorders are emerging.
BT - Biological Psychiatry
DA - 2023-04-01
DO - 10.1016/j.biopsych.2023.01.012
IS - 7
N2 - The past decade has seen an explosion in the identification of genetic causes of neurodevelopmental disorders, including Mendelian, de novo, and somatic factors. These discoveries provide opportunities to understand cellular and molecular mechanisms as well as potential gene-gene and gene-environment interactions to support novel therapies. Stem cell–based models, particularly human brain organoids, can capture disease-associated alleles in the context of the human genome, engineered to mirror disease-relevant aspects of cellular complexity and developmental timing. These models have brought key insights into neurodevelopmental disorders as diverse as microcephaly, autism, and focal epilepsy. However, intrinsic organoid-to-organoid variability, low levels of certain brain-resident cell types, and long culture times required to reach maturity can impede progress. Several recent advances incorporate specific morphogen gradients, mixtures of diverse brain cell types, and organoid engraftment into animal models. Together with nonhuman primate organoid comparisons, mechanisms of human neurodevelopmental disorders are emerging.
PY - 2023
SP - 622
EP - 631
T2 - Biological Psychiatry
TI - Stem Cell–Based Organoid Models of Neurodevelopmental Disorders
UR - https://www.sciencedirect.com/science/article/pii/S0006322323000392
VL - 93
Y2 - 2023-09-15
SN - 0006-3223
ER -