Stem cell-based region-specific brain organoids: Novel models to understand neurodevelopmental defects

The study of human brain development and neurodevelopmental defects has remained challenging so far due to unique, specific, and complex underlying processes. Recent advances in the technologies and protocols of in vitro human brain organoid development have led to immense possibilities of understanding these processes. Human brain organoids are stem-cell derived three-dimensional in vitro tissues that resemble the developing fetal brain. Major advances in stem cell techniques pioneering the development of in vitro human brain development include reprogramming human somatic cells into induced pluripotent cells (iPSCs) followed by the targeted differentiation of iPSCs into the cells of three embryonic germ cell layers. The neural progenitor cells produced by the directed differentiation of iPSCs undergo some level of self-organization to generate in vitro human brain like tissue. A three-dimensional differentiation approach applied to create region-specific brain organoids has successfully led to develop highly specialized cortical, forebrain, pallium, and subpallium in vitro human brain organoid models. These stem cell-based brain organoids are novel models to study human brain development, neurodevelopmental defects, chemical toxicity testing, and drug repurposing screening. This review focuses on the fundamentals of brain organoid development and applications. The novel applications of using cortical organoids in understanding the mechanisms of Zika virus-induced microcephaly, congenital microcephaly, and lissencephaly are also discussed.