Strengths and Challenges of Human Cell Models of Neurodevelopmental Disorders

Human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and particularly induced PSCs (iPSCs) from patients, have tremendous potential to unveil cellular and molecular events underlying normal and abnormal neural development as well as to understand neurological disease pathogenesis in a human genetic background. The power of human PSCs to model human brain development lies in the ability to generate specific neural cell types in vitro over a period of time that corresponds to in vivo development, thus recapitulating many of the developmental steps. Yet, there are challenges in using these cells for neurodevelopmental disorder modeling including distinguishing biologically relevant changes leading to complex traits from those resulting from variability between human PSCs, limited maturation of neurons and experimental reproducibility. I will highlight our work using human PSCs to investigate human-specific biology and disease mechanisms in Down syndrome and Fragile X syndrome. Because these two disorders are characterized by mutations unique to humans, human cell models are critical. We rely on the power of isogenic stem cells, co-cultures and rigorous methods to address the challenges of these cells. Understanding how mistakes in neural development in both these disorders result in cognitive disability may enable us to intelligently design therapies to positively impact individuals and families living with them.