Human cerebral organoids — a new tool for clinical neurology research

Abstract

The current understanding of neurological diseases is derived mostly from direct analysis of patients and from animal models of disease. However, most patient studies do not capture the earliest stages of disease development and offer limited opportunities for experimental intervention, so rarely yield complete mechanistic insights. The use of animal models relies on evolutionary conservation of pathways involved in disease and is limited by an inability to recreate human-specific processes. In vitro models that are derived from human pluripotent stem cells cultured in 3D have emerged as a new model system that could bridge the gap between patient studies and animal models. In this Review, we summarize how such organoid models can complement classical approaches to accelerate neurological research. We describe our current understanding of neurodevelopment and how this process differs between humans and other animals, making human-derived models of disease essential. We discuss different methodologies for producing organoids and how organoids can be and have been used to model neurological disorders, including microcephaly, Zika virus infection, Alzheimer disease and other neurodegenerative disorders, and neurodevelopmental diseases, such as Timothy syndrome, Angelman syndrome and tuberous sclerosis. We also discuss the current limitations of organoid models and outline how organoids can be used to revolutionize research into the human brain and neurological diseases.

Special properties of adult neurogenesis in the human hippocampus: Implications for its clinical applications

“…Not only did we observe substantial variance in imN‐enriched molecular signatures, we also found cell dynamics regarding transcriptomic shifts associated with age and potentially prolonged maturation in human imNs 5 . Such cross‐species differences in various aspects have been widely observed in other brain regions (e.g., the developing neocortex) in humans in comparison with other species, such as mice and non‐human primates 8,9 . Therefore, direct analyses of human brain tissue or human‐based model systems are critical to examine mechanisms, pathologies, treatment strategies, and functions of human biological processes and diseases, including adult human neurogenesis.…”

“…5 Our results support continuous hippocampal neurogenesis in humans and suggest a model for retaining a large pool of imNs in the adult human hippocampus by low-frequency de novo generation of neural progenitors and prolonged maturation of imNs (Figure 1A,C). 5 Significant species differences revealed in our study 5 (Figure 1C), and others 8,9 highlight limitations of using classic models, such as mice, to fully recapitulate features of human brain development or disorders, or to predict the impact of therapeutic treatment on human diseases.…”

“… 5 Such cross‐species differences in various aspects have been widely observed in other brain regions (e.g., the developing neocortex) in humans in comparison with other species, such as mice and non‐human primates. 8 , 9 Therefore, direct analyses of human brain tissue or human‐based model systems are critical to examine mechanisms, pathologies, treatment strategies, and functions of human biological processes and diseases, including adult human neurogenesis. In recent years, procurement of high‐quality human brain specimens and advances in human pluripotent stem cell (hPSC)‐based model systems provide unprecedented opportunities to directly examine human brain development and diseases to understand their underlying cellular and molecular mechanisms (Figure 1D ).…”

“…In recent years, procurement of high‐quality human brain specimens and advances in human pluripotent stem cell (hPSC)‐based model systems provide unprecedented opportunities to directly examine human brain development and diseases to understand their underlying cellular and molecular mechanisms (Figure 1D ). 8 , 9 Despite the constraints of all emerging human models, such as the limited ability to study circuitry and behaviour, and an incomplete cell diversity recapitulated in the in vitro or ex vivo model systems, these technological advances, including neuropathological examination of patient specimens, patient surgical specimens for acute or organotypic slice culture, 2D and 3D hPSC‐derived models (e.g., brain organoids), and xenograft systems, 8 , 9 will bridge the gap between patient studies and animal models to revolutionize the study of brain development and diseases and therapeutic compound development in the next decade (Figure 1D ).…”

Morphogenesis and development of human telencephalic organoids in the absence and presence of exogenous ECM

“…Key features of neuroepithelium generation, morphogenesis, and differentiation can be recapitulated with brain organoids, three-dimensional models of developing human brain regions ( Eichmüller & Knoblich , 2022; Pasca , 2018; Quadrato & Arlotta , 2017; Sidhaye & Knoblich , 2021). In vitro systems of various epithelial tissues are able to model aspects of endogenous morphogenesis with remarkable accuracy, but often lack endogenous ECM production, therefore requiring exogenous ECM supplementation ( Corsini & Knoblich , 2022; Inman & Bissell , 2010; Kratochvil et al ., 2019; Simian & Bissell , 2017).…”