Human Cerebral Organoids and Fetal Brain Tissue Share Proteomic Similarities

Nascimento, Juliana; Saia-Cereda, Verônica M.; Sartore, Rafaela C.; Costa, Rodrigo Madeiro da; Schitine, Clarissa; Freitas, Hércules Rezende; Murgu, Michael; Reis, Ricardo Augusto de Melo; Rehen, Stevens K.; Martins‐de‐Souza, Daniel

doi:10.3389/fcell.2019.00303

Cited by 73 publications

(65 citation statements)

References 68 publications

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“…Differentiation of iPS on neural cells from self-organized human organoids/spheroids has recently been used to generate multiple classes of cells: progenitors, neurons, and glia to be enriched and considered to be used in healthy and disease models, such as neurological disorders. Indeed astrocyte ( Dezonne et al, 2017 ; Sloan et al, 2017 ), oligodendrocyte ( Marton et al, 2019 ) and neuron ( Nascimento et al, 2019 ) lineage cells, as well as region-specific cortical neurons and astrocytes, some from both deep and superficial cortical layers that are transcriptionally correlated to in vivo fetal development ( Paşca et al, 2015 ), have been generated following multiple strategies, of which functionality data included calcium imaging assays. Derived glia from human cerebral cortical spheroids had similar properties found in primary fetal astrocytes, and upon transition to a more developed state, dozens of astrocytic markers increased as expected, accelerating around birth, while fetal astrocyte markers declined rapidly over this same period.…”

Section: Neural Cell Lineages Derived From Ips Cellsmentioning

confidence: 99%

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

2020

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Complex dynamic cellular networks have been studied in physiological and pathological processes under the light of single-cell calcium imaging (SCCI), a method that correlates functional data based on calcium shifts operated by different intracellular and extracellular mechanisms integrated with their cell phenotypes. From the classic synaptic structure to tripartite astrocytic model or the recent quadripartite microglia added ensemble, as well as other physiological tissues, it is possible to follow how cells signal spatiotemporally to cellular patterns. This methodology has been used broadly due to the universal properties of calcium as a second messenger. In general, at least two types of receptor operate through calcium permeation: a fast-acting ionotropic receptor channel and a slow-activating metabotropic receptor, added to exchangers/transporters/pumps and intracellular Ca 2+ release activated by messengers. These prototypes have gained an enormous amount of information in dynamic signaling circuits. SCCI has also been used as a method to associate phenotypic markers during development and stage transitions in progenitors, stem, vascular cells, neuro- and glioblasts, neurons, astrocytes, oligodendrocytes, and microglia that operate through ion channels, transporters, and receptors. Also, cancer cells or inducible cell lines from human organoids characterized by transition stages are currently being used to model diseases or reconfigure healthy cells in terms of the expression of calcium-binding/permeable molecules and shed light on therapy.

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Section: Neural Cell Lineages Derived From Ips Cellsmentioning

confidence: 99%

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

2020

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“…4 a). SEMA6D is expressed during brain development and is related to neural circuits [ 24 ] and axonal guidance [ 25 ]. The retention of ancestral sequences was related to a reduction in education attainment years and associated with the downregulation of the SEMA6D in brain tissue (see the “ Methods ” section; β = − 0.70, SE = 0.11, p value = 6.2 × 10 −9 ; Fig.…”

Section: Resultsmentioning

confidence: 99%

Insertion variants missing in the human reference genome are widespread among human populations

Lee

Kim

et al. 2020

BMC Biol

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Background Structural variants comprise diverse genomic arrangements including deletions, insertions, inversions, and translocations, which can generally be detected in humans through sequence comparison to the reference genome. Among structural variants, insertions are the least frequently identified variants, mainly due to ascertainment bias in the reference genome, lack of previous sequence knowledge, and low complexity of typical insertion sequences. Though recent developments in long-read sequencing deliver promise in annotating individual non-reference insertions, population-level catalogues on non-reference insertion variants have not been identified and the possible functional roles of these hidden variants remain elusive. Results To detect non-reference insertion variants, we developed a pipeline, InserTag, which generates non-reference contigs by local de novo assembly and then infers the full-sequence of insertion variants by tracing contigs from non-human primates and other human genome assemblies. Application of the pipeline to data from 2535 individuals of the 1000 Genomes Project helped identify 1696 non-reference insertion variants and re-classify the variants as retention of ancestral sequences or novel sequence insertions based on the ancestral state. Genotyping of the variants showed that individuals had, on average, 0.92-Mbp sequences missing from the reference genome, 92% of the variants were common (allele frequency > 5%) among human populations, and more than half of the variants were major alleles. Among human populations, African populations were the most divergent and had the most non-reference sequences, which was attributed to the greater prevalence of high-frequency insertion variants. The subsets of insertion variants were in high linkage disequilibrium with phenotype-associated SNPs and showed signals of recent continent-specific selection. Conclusions Non-reference insertion variants represent an important type of genetic variation in the human population, and our developed pipeline, InserTag, provides the frameworks for the detection and genotyping of non-reference sequences missing from human populations.

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“…Cerebral organoids mimic transcriptional and proteomic signatures of fetal brain development and have grown in popularity as excellent models to understand neurodevelopmental disorders in humans (Camp et al, 2015 ; Kelava and Lancaster, 2016 ; Luo et al, 2016 ; Kanton et al, 2019 ; Nascimento et al, 2019 ; Logan et al, 2020 ). Recently cerebral organoids were infected with SARS-CoV-2 providing the first evidence of neurotropism in in vitro cultures (Jacob et al, 2020 ; Pellegrini et al, 2020 ; Ramani et al, 2020 ; Song et al, 2020 ; Zhang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Novel Targets of SARS-CoV-2 Spike Protein in Human Fetal Brain Development Suggest Early Pregnancy Vulnerability

et al. 2021

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Pregnant women are at greater risk of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), because of their altered immunity and strained cardiovascular system. Emerging studies of placenta, embryos, and cerebral organoids suggest that fetal organs including brain could also be vulnerable to coronavirus disease 2019 (COVID-19). Additionally, a case study from Paris has reported transient neurological complications in neonates born to pregnant mothers. However, it remains poorly understood whether the fetal brain expresses cellular components that interact with Spike protein (S) of coronaviruses, which facilitates fusion of virus and host cell membrane and is the primary protein in viral entry. To address this question, we analyzed the expression of known (ACE2, TMPRSS2, and FURIN) and novel (ZDHHC5, GOLGA7, and ATP1A1) S protein interactors in publicly available fetal brain bulk and single cell RNA sequencing datasets. Bulk RNA sequencing analysis across multiple regions of fetal brain spanning 8 weeks post conception (wpc)−37wpc indicates that two of the known S protein interactors are expressed at low levels with median normalized gene expression values ranging from 0.08 to 0.06 (ACE2) and 0.01–0.02 (TMPRSS2). However, the third known S protein interactor FURIN is highly expressed (11.1–44.09) in fetal brain. Interestingly, all three novel S protein interactors are abundantly expressed throughout fetal brain development with median normalized gene expression values ranging from 20.38–21.60 (ZDHHC5), 92.47–68.35 (GOLGA7), and 65.45–194.5 (ATP1A1). Moreover, the peaks of expression of novel interactors is around 12–26wpc. Using publicly available single cell RNA sequencing datasets, we further show that novel S protein interactors show higher co-expression with neurons than with neural progenitors and astrocytes. These results suggest that even though two of the known S protein interactors are present at low levels in fetal brain, novel S protein interactors are abundantly present and could play a direct or indirect role in SARS-CoV-2 fetal brain pathogenesis, especially during the 2nd and 3rd trimesters of pregnancy.

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Human Cerebral Organoids and Fetal Brain Tissue Share Proteomic Similarities

Cited by 73 publications

References 68 publications

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

Insertion variants missing in the human reference genome are widespread among human populations

Novel Targets of SARS-CoV-2 Spike Protein in Human Fetal Brain Development Suggest Early Pregnancy Vulnerability

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