3D Brain Organoids: Studying Brain Development and Disease Outside the Embryo

2020 ◽  
Vol 43 (1) ◽  
pp. 375-389 ◽  
Author(s):  
Silvia Velasco ◽  
Bruna Paulsen ◽  
Paola Arlotta
Keyword(s):  
Stem Cell ◽  
Human Brain ◽  
Brain Development ◽  
Neurological Disease ◽  
Three Dimensional ◽  
Experimental Models ◽  
Brain Pathology ◽  
Molecular Events ◽  
In Utero Development ◽  
Experimental Strategies

Scientists have been fascinated by the human brain for centuries, yet knowledge of the cellular and molecular events that build the human brain during embryogenesis and of how abnormalities in this process lead to neurological disease remains very superficial. In particular, the lack of experimental models for a process that largely occurs during human in utero development, and is therefore poorly accessible for study, has hindered progress in mechanistic understanding. Advances in stem cell–derived models of human organogenesis, in the form of three-dimensional organoid cultures, and transformative new analytic technologies have opened new experimental pathways for investigation of aspects of development, evolution, and pathology of the human brain. Here, we consider the biology of brain organoids, compared and contrasted with the endogenous human brain, and highlight experimental strategies to use organoids to pioneer new understanding of human brain pathology.

scholarly journals Three-dimensional induced pluripotent stem-cell models of human brain angiogenesis

2020 ◽  
Vol 132 ◽  
pp. 104042 ◽  
Author(s):  
Raleigh M. Linville ◽  
Diego Arevalo ◽  
Joanna C. Maressa ◽  
Nan Zhao ◽  
Peter C. Searson
Keyword(s):  
Stem Cell ◽  
Human Brain ◽  
Pluripotent Stem Cell ◽  
Three Dimensional ◽  
Induced Pluripotent Stem Cell ◽  
Cell Models ◽  
Induced Pluripotent ◽  
Stem Cell Models ◽  
Brain Angiogenesis

scholarly journals Challenges in Modeling Human Neural Circuit Formation via Brain Organoid Technology

2020 ◽  
Vol 14 ◽  
Author(s):  
Takeshi K. Matsui ◽  
Yuichiro Tsuru ◽  
Ken-ichiro Kuwako
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Neural Circuit ◽  
Disease Modeling ◽  
Three Dimensional ◽  
Neural Lineage ◽  
Human Brain Development ◽  
Brain Organoid ◽  
Circuit Formation

Human brain organoids are three-dimensional self-organizing tissues induced from pluripotent cells that recapitulate some aspects of early development and some of the early structure of the human brain in vitro. Brain organoids consist of neural lineage cells, such as neural stem/precursor cells, neurons, astrocytes and oligodendrocytes. Additionally, brain organoids contain fluid-filled ventricle-like structures surrounded by a ventricular/subventricular (VZ/SVZ) zone-like layer of neural stem cells (NSCs). These NSCs give rise to neurons, which form multiple outer layers. Since these structures resemble some aspects of structural arrangements in the developing human brain, organoid technology has attracted great interest in the research fields of human brain development and disease modeling. Developmental brain disorders have been intensely studied through the use of human brain organoids. Relatively early steps in human brain development, such as differentiation and migration, have also been studied. However, research on neural circuit formation with brain organoids has just recently began. In this review, we summarize the current challenges in studying neural circuit formation with organoids and discuss future perspectives.

scholarly journals Modeling HIV-1 neuropathogenesis using three-dimensional human brain organoids (hBORGs) with HIV-1 infected microglia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Roberta S. dos Reis ◽  
Shilpa Sant ◽  
Hannah Keeney ◽  
Marc C. E. Wagner ◽  
Velpandi Ayyavoo
Keyword(s):  
Human Brain ◽  
Interleukin 1 ◽  
Three Dimensional ◽  
Cell Types ◽  
Great Promise ◽  
Experimental Systems ◽  
Molecular Events ◽  
Hiv Neuropathogenesis ◽  
Brain Organoid ◽  
Hiv 1

Abstract HIV-1 associated neurocognitive disorder (HAND) is characterized by neuroinflammation and glial activation that, together with the release of viral proteins, trigger a pathogenic cascade resulting in synaptodendritic damage and neurodegeneration that lead to cognitive impairment. However, the molecular events underlying HIV neuropathogenesis remain elusive, mainly due to lack of brain-representative experimental systems to study HIV-CNS pathology. To fill this gap, we developed a three-dimensional (3D) human brain organoid (hBORG) model containing major cell types important for HIV-1 neuropathogenesis; neurons and astrocytes along with incorporation of HIV-infected microglia. Both infected and uninfected microglia infiltrated into hBORGs resulting in a triculture system (MG-hBORG) that mirrors the multicellular network observed in HIV-infected human brain. Moreover, the MG-hBORG model supported productive viral infection and exhibited increased inflammatory response by HIV-infected MG-hBORGs, releasing tumor necrosis factor (TNF-α) and interleukin-1 (IL-1β) and thereby mimicking the chronic neuroinflammatory environment observed in HIV-infected individuals. This model offers great promise for basic understanding of how HIV-1 infection alters the CNS compartment and induces pathological changes, paving the way for discovery of biomarkers and new therapeutic targets.

Convergence of human pluripotent stem cell, organoid, and genome editing technologies

2021 ◽  
pp. 153537022098580
Author(s):  
Lin Wang ◽  
Zhaohui Ye ◽  
Yoon-Young Jang
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Genome Editing ◽  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Three Dimensional ◽  
Experimental Models ◽  
Human Pluripotent Stem Cell ◽  
Research Areas ◽  
Technological Advances

The last decade has seen many exciting technological breakthroughs that greatly expanded the toolboxes for biological and biomedical research, yet few have had more impact than induced pluripotent stem cells and modern-day genome editing. These technologies are providing unprecedented opportunities to improve physiological relevance of experimental models, further our understanding of developmental processes, and develop novel therapies. One of the research areas that benefit greatly from these technological advances is the three-dimensional human organoid culture systems that resemble human tissues morphologically and physiologically. Here we summarize the development of human pluripotent stem cells and their differentiation through organoid formation. We further discuss how genetic modifications, genome editing in particular, were applied to answer basic biological and biomedical questions using organoid cultures of both somatic and pluripotent stem cell origins. Finally, we discuss the potential challenges of applying human pluripotent stem cell and organoid technologies for safety and efficiency evaluation of emerging genome editing tools.

scholarly journals A human stem cell resource to decipher the biochemical and cellular basis of neurodevelopmental defects in Lowe Syndrome

Biology Open ◽  
2022 ◽  
Author(s):  
Bilal M. Akhtar ◽  
Priyanka Bhatia ◽  
Shubhra Acharya ◽  
Sanjeev Sharma ◽  
Yojet Sharma ◽  
...  
Keyword(s):  
Stem Cell ◽  
Lipid Metabolism ◽  
Human Brain ◽  
Brain Development ◽  
Cell Lines ◽  
Brain Function ◽  
Lowe Syndrome ◽  
Human Stem Cell ◽  
Human Brain Development ◽  
Developmental Features

Human brain development is a complex process where multiple cellular and developmental events are co-ordinated to generate normal structure and function. Alteration in any of these events can impact brain development, manifesting clinically as neurodevelopmental disorders. Human genetic disorders of lipid metabolism often present with features of altered brain function. Lowe syndrome (LS), is a X-linked recessive disease with features of altered brain function. LS results from mutations in OCRL1 that encodes a phosphoinositide 5-phosphatase enzyme. However, the cellular mechanisms by which loss of OCRL1 leads to brain defects remain unknown. Human brain development involves several cellular and developmental features not conserved in other species and understanding such mechanisms remains a challenge. Rodent models of LS have been generated, but failed to recapitulate features of the human disease. Here we describe the generation of human stem cell lines from LS patients. Further, we present biochemical characterization of lipid metabolism in patient cell lines and demonstrate their use as a “disease-in-a-dish” model for understanding the mechanism by which loss of OCRL1 leads to altered cellular and physiological brain development.

scholarly journals A human stem cell resource to decipher the biochemical and cellular basis of neurodevelopmental defects in Lowe Syndrome

2021 ◽  
Author(s):  
Bilal Akhtar ◽  
Priyanka Bhatia ◽  
Shubhra Acharya ◽  
Sanjeev Sharma ◽  
Yojet Sharma ◽  
...  
Keyword(s):  
Stem Cell ◽  
Lipid Metabolism ◽  
Human Brain ◽  
Brain Development ◽  
Cell Lines ◽  
Brain Function ◽  
Lowe Syndrome ◽  
Human Stem Cell ◽  
Human Brain Development ◽  
Developmental Features

Human brain development is a complex process where multiple cellular and developmental events are co-ordinated to generate normal structure and function. Alteration in any of these events can impact brain development, manifesting clinically as neurodevelopmental disorders. Human genetic disorders of lipid metabolism often present with features of altered brain function. Lowe syndrome (LS), is a X-linked recessive disease with features of altered brain function. LS results from mutations in OCRL1 that encodes a phosphoinositide 5-phosphatase enzyme. However, the cellular mechanisms by which loss of OCRL1 leads to brain defects remain unknown. Human brain development involves several cellular and developmental features not conserved in other species and understanding such mechanisms remains a challenge. Rodent models of LS have been generated, but failed to recapitulate features of the human disease. Here we describe the generation of human stem cell lines from LS patients. Further, we present biochemical characterization of lipid metabolism in patient cell lines and demonstrate their use as a disease-in-a-dish model for understanding the mechanism by which loss of OCRL1 leads to altered cellular and physiological brain development.

Three-dimensional models of human brain development

2020 ◽  
pp. 257-278
Author(s):  
Alejandro Lopez-Tobon ◽  
Nicolò Caporale ◽  
Sebastiano Trattaro ◽  
Giuseppe Testa
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Three Dimensional ◽  
Human Brain Development ◽  
Dimensional Models ◽  
Three Dimensional Models

scholarly journals Characterization of the ventricular-subventricular stem cell niche during human brain development

Development ◽  
2018 ◽  
Vol 145 (20) ◽  
pp. dev170100 ◽  
Author(s):  
Amanda M. Coletti ◽  
Deepinder Singh ◽  
Saurabh Kumar ◽  
Tasnuva Nuhat Shafin ◽  
Patrick J. Briody ◽  
...  
Keyword(s):  
Stem Cell ◽  
Human Brain ◽  
Brain Development ◽  
Stem Cell Niche ◽  
Human Brain Development ◽  
Cell Niche

scholarly journals Cerebral organoids: a promising model in cellular technologies

2018 ◽  
Vol 22 (2) ◽  
pp. 168-178
Author(s):  
T. A. Shnaider
Keyword(s):  
Stem Cell ◽  
Human Brain ◽  
Brain Region ◽  
Pluripotent Stem Cell ◽  
Three Dimensional ◽  
Brain Regions ◽  
Cortical Plate ◽  
Successful Implementation ◽  
Human Pluripotent Stem Cell ◽  
Long Distance

The development of the human brain is a complex multi-stage process including the formation of various types of neural cells and their interactions. Many fundamental mechanisms of neurogenesis have been established due to the studying of model animals. However, significant differences in the brain structure compared to other animals do not allow considering all aspects of the human brain formation, which could play the main role in the development of unique cognitive abilities for human. Four years ago, Lancaster’s group elaborated human pluripotent stem cell-derived three-dimensional cerebral organoid technology, which opened a unique opportunity for researchers to model early stages of human neurogenesis in vitro. Cerebral organoids closely remodel many endogenous brain regions with specific cell composition like ventricular zone with radial glia, choroid plexus, and cortical plate with upper and deeper-layer neurons. Moreover, human brain development includes interactions between different brain regions. Generation of hybrid three-dimensional cerebral organoids with different brain region identity allows remodeling some of them, including long-distance neuronal migration or formation of major axonal tracts. In this review, we consider the technology of obtaining human pluripotent stem cell-derived three-dimensional cerebral organoids with different modifications and with different brain region identity. In addition, we discuss successful implementation of this technology in fundamental and applied research like modeling of different neurodevelopmental disorders and drug screening. Finally, we regard existing problems and prospects for development of human pluripotent stem cell-derived threedimensional cerebral organoid technology.

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