Stem Cell-Based Organoid Models of Neurodevelopmental Disorders.

Scientists are using lab-grown brain tissue called 'organoids' to better understand developmental conditions like autism. These mini-brain models help researchers study how genetic changes affect brain development in ways similar to human brains. While this research has provided new insights into autism and other conditions, the technology still has challenges like inconsistency between samples and long growing times.

This review examines the use of human brain organoids - laboratory-grown brain tissue models - to study neurodevelopmental disorders including autism. The authors highlight how genetic discoveries over the past decade have enabled researchers to create organoid models that capture disease-causing genetic variations within human brain development contexts. These models have provided insights into disorders like microcephaly, autism, and focal epilepsy by allowing researchers to observe cellular and molecular mechanisms in controlled conditions. The review identifies current limitations including variability between organoids, underrepresentation of certain brain cell types, and lengthy maturation periods.

Recent advances include improved cultivation methods using specific growth factors, incorporating diverse brain cell types, and transplanting organoids into animal models to better understand human neurodevelopmental disorders.

Brain organoid models offer promising avenues for understanding autism mechanisms and testing potential therapies. However, current limitations must be addressed before reliable clinical applications can emerge. These models may eventually support personalized medicine approaches and drug development for neurodevelopmental disorders.

Current limitations include significant organoid-to-organoid variability, underrepresentation of certain brain cell types, and lengthy culture periods required for maturation. These factors can impede research progress and limit the reliability of findings.

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.