Brain Organoids: Expanding Our Understanding of Human Development and Disease

Abstract

Stem cell-derived brain organoids replicate important stages of the prenatal human brain development and combined with the induced pluripotent stem cell (iPSC) technology offer an unprecedented model for investigating human neurological diseases including autism and microcephaly. We describe the history and birth of organoids and their application, focusing on cerebral organoids derived from embryonic stem cells and iPSCs. We discuss new insights into organoid-based model of schizophrenia and shed light on challenges and future applications of organoid-based disease model system. This review also suggests hitherto unrevealed potential applications of organoids in combining with new technologies such as nanophotonics/optogenomics for controlling brain development and atomic force microscopy for studying mechanical forces that shape the developing brain.

Immune Factor, TNFα, Disrupts Human Brain Organoid Development Similar to Schizophrenia—Schizophrenia Increases Developmental Vulnerability to TNFα

“…Both genetic factors, as well as physical and psychosocial environmental factors play a role in the development of SZ. The combined effect of genetics and environmental factors leads to abnormal circuit formation and consequently, aberrant neurotransmitter and synaptic function and ultimately abnormal behavior in SZ (Na et al, 2014 ; Estes and McAllister, 2016 ; Chuye et al, 2018 ). Evidence points to the primary hypothesis of convergence, in which genes and environmental factors converge and disrupt common developmental mechanism(s) leading to the emergence of SZ (Clarke et al, 2006 ; Schmitt et al, 2011 ).…”

“…In order to better understand the neurodevelopment of SZ, organoids, or “mini brains,” generated from patient iPSC, provided for the first time, an insight into early disease etiology, parallel to the in utero development of the fetal brain during disease development (Stachowiak et al, 2017 ). These cerebral organoids mimic and closely model human brain development by generating the cerebral cortex, ventral telencephalon, choroid plexus, and retinal identities, among other brain regions (Chuye et al, 2018 ). The production of organoids in vitro can be used for studies of migration, differentiation, basic early neurodevelopment, as well as disease development and progression.…”

“…The cerebral organoids allowed for the first time to relate the broad INFS-linked transcriptional dysregulations found in SZ iPSC neural progenitor cells (NPCs; Narla et al, 2017 ) to development of the human brain malformations in SZ phenotype (Stachowiak et al, 2017 ). These genomic and tissue structural dysregulations were found in patients with different genomic backgrounds and may constitute a common developmental signature of the SZ phenotype (Chuye et al, 2018 ; Narla et al, 2018 ).…”

Increased Tau Expression Correlates with Neuronal Maturation in the Developing Human Cerebral Cortex

“…Induced pluripotent stem cell (iPSC)-derived human brain organoids have become a key tool in developmental neurobiology (Amin and Paşca, 2018;Chuye et al, 2018). Human cortical organoids described by Yoon et al (2019) and Pasca et al (2015) are region-specific brain organoids derived through directed differentiation methods to generate dorsal forebrain progenitors, pyramidal cortical neurons, and astrocytes (Pasca et al, 2015;Yoon et al, 2019) Extensive characterization of human cortical organoids through single-cell analyses, transcriptional profiling, and histologic assays demonstrated cytoarchitectural inside-out organization resembling the developing human dorsal forebrain and progressive in vitro differentiation of progenitors into pyramidal neurons of multiple cortical layers and astrocytes (Pasca et al, 2015;Sloan et al, 2017;Yoon et al, 2019).…”

Hidden Aspects of the Research-ADOS are Bound to Affect Autism Science

“…to characterize genetics, brain activity and somatic-sensory-motor issues across different imaging and wearable sensors platforms, e.g. [5; 6; 30; 31; 32; 33; 34]) is that there is always a group of neurotypical controls included in the study. This is so, to help us establish normative data and to ascertain departure from it across the human lifespan.…”