Human organoids to model the developing human neocortex in health and disease

Khakipoor, Shokoufeh; Crouch, Elizabeth E.; Mayer, Simone

doi:10.1016/j.brainres.2020.146803

Cited by 14 publications

(13 citation statements)

References 95 publications

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“…Platforms to survey the function of vascular cells are also lacking. While organoids have rapidly increased in popularity to study neuronal brain cell types, these “mini-brains” have only been vascularized with ECs from other organs to date and further lack blood flow ( Khakipoor et al, 2020 ). Regulatory mechanism responsible for the genesis or maintenance of transcriptomic diversity in the context of brain vascular cells is also presently poorly defined.…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

The Expanding Cell Diversity of the Brain Vasculature

et al. 2020

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The cerebrovasculature is essential to brain health and is tasked with ensuring adequate delivery of oxygen and metabolic precursors to ensure normal neurologic function. This is coordinated through a dynamic, multi-directional cellular interplay between vascular, neuronal, and glial cells. Molecular exchanges across the blood–brain barrier or the close matching of regional blood flow with brain activation are not uniformly assigned to arteries, capillaries, and veins. Evidence has supported functional segmentation of the brain vasculature. This is achieved in part through morphologic or transcriptional heterogeneity of brain vascular cells—including endothelium, pericytes, and vascular smooth muscle. Advances with single cell genomic technologies have shown increasing cell complexity of the brain vasculature identifying previously unknown cell types and further subclassifying transcriptional diversity in cardinal vascular cell types. Cell-type specific molecular transitions or zonations have been identified. In this review, we summarize emerging evidence for the expanding vascular cell diversity in the brain and how this may provide a cellular basis for functional segmentation along the arterial-venous axis.

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Section: Discussion and Future Directionsmentioning

confidence: 99%

The Expanding Cell Diversity of the Brain Vasculature

et al. 2020

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“…Morphogens used to guide dorsal forebrain identity include TGF-β, Wnt and BMP pathway inhibitors ( Kadoshima et al, 2013 ; Paşca et al, 2015 ; Velasco et al, 2019 ) while BMP and Wnt pathway activators are required for induction of choroid plexus identity ( Pellegrini et al, 2020b ). A more detailed review of the different organoid differentiation protocols can be found elsewhere ( Qian et al, 2019 ; Khakipoor et al, 2020 ).…”

Section: Major Populations Of Cortical Neural Stem Cells Can Be Found In Brain Organoidsmentioning

confidence: 99%

“…Brain organoids are a promising model system, but do not fully recapitulate human brain development in vivo . First, they lack the cells not originating from neuroectoderm, such as those of the vasculature and microglia ( Khakipoor et al, 2020 ). Specifically, the vasculature is important for the proper modeling of fetal brain hypoxia with brain organoids.…”

Section: Technological Advances Drive Progress In Brain Organoid Research and Increase Interpretability Across Studiesmentioning

confidence: 99%

The Effects of Environmental Adversities on Human Neocortical Neurogenesis Modeled in Brain Organoids

Sarieva

Mayer

2021

Front. Mol. Biosci.

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Over the past decades, a growing body of evidence has demonstrated the impact of prenatal environmental adversity on the development of the human embryonic and fetal brain. Prenatal environmental adversity includes infectious agents, medication, and substances of use as well as inherently maternal factors, such as diabetes and stress. These adversities may cause long-lasting effects if occurring in sensitive time windows and, therefore, have high clinical relevance. However, our knowledge of their influence on specific cellular and molecular processes of in utero brain development remains scarce. This gap of knowledge can be partially explained by the restricted experimental access to the human embryonic and fetal brain and limited recapitulation of human-specific neurodevelopmental events in model organisms. In the past years, novel 3D human stem cell-based in vitro modeling systems, so-called brain organoids, have proven their applicability for modeling early events of human brain development in health and disease. Since their emergence, brain organoids have been successfully employed to study molecular mechanisms of Zika and Herpes simplex virus-associated microcephaly, as well as more subtle events happening upon maternal alcohol and nicotine consumption. These studies converge on pathological mechanisms targeting neural stem cells. In this review, we discuss how brain organoids have recently revealed commonalities and differences in the effects of environmental adversities on human neurogenesis. We highlight both the breakthroughs in understanding the molecular consequences of environmental exposures achieved using organoids as well as the on-going challenges in the field related to variability in protocols and a lack of benchmarking, which make cross-study comparisons difficult.

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“…The key characteristics of cerebral organoids are the ability of stem cells to produce self-organized structures resembling various brain regions. This methodology is based on the production of embryonic bodies and clusters of neuroepithelial cells followed by the establishment of apico-basally polarized neural tissue that is achieved by so-called un-guided or guided protocols to get spontaneous differentiation or specification of cell development, respectively [93]. The main advantage in using human iPSC-derived cerebral organoids is an opportunity to get the human-specific cell types and tissue developmental traits that could not be reproduced in the rodent tissue [94].…”

Section: Generation Of Ipsc-derived Midbrain Cerebral Organoidsmentioning

confidence: 99%

Novel Approaches Used to Examine and Control Neurogenesis in Parkinson′s Disease

Салмина

Kapkaeva

Ветчинова

et al. 2021

IJMS

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Neurogenesis is a key mechanism of brain development and plasticity, which is impaired in chronic neurodegeneration, including Parkinson’s disease. The accumulation of aberrant α-synuclein is one of the features of PD. Being secreted, this protein produces a prominent neurotoxic effect, alters synaptic plasticity, deregulates intercellular communication, and supports the development of neuroinflammation, thereby providing propagation of pathological events leading to the establishment of a PD-specific phenotype. Multidirectional and ambiguous effects of α-synuclein on adult neurogenesis suggest that impaired neurogenesis should be considered as a target for the prevention of cell loss and restoration of neurological functions. Thus, stimulation of endogenous neurogenesis or cell-replacement therapy with stem cell-derived differentiated neurons raises new hopes for the development of effective and safe technologies for treating PD neurodegeneration. Given the rapid development of optogenetics, it is not surprising that this method has already been repeatedly tested in manipulating neurogenesis in vivo and in vitro via targeting stem or progenitor cells. However, niche astrocytes could also serve as promising candidates for controlling neuronal differentiation and improving the functional integration of newly formed neurons within the brain tissue. In this review, we mainly focus on current approaches to assess neurogenesis and prospects in the application of optogenetic protocols to restore the neurogenesis in Parkinson’s disease.

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Human organoids to model the developing human neocortex in health and disease

Cited by 14 publications

References 95 publications

The Expanding Cell Diversity of the Brain Vasculature

The Expanding Cell Diversity of the Brain Vasculature

The Effects of Environmental Adversities on Human Neocortical Neurogenesis Modeled in Brain Organoids

Novel Approaches Used to Examine and Control Neurogenesis in Parkinson′s Disease

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