Integrated spatial transcriptome and metabolism study reveals metabolic heterogeneity in human injured brain

Cell Reports Medicine, Journal Year: 2023, Volume and Issue: 4(6), P. 101057 - 101057

Published: May 31, 2023

Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in brain. With advances multi-omics datasets, a major challenge is to validate and integrate results into biological understanding spatial organization functional orientation. Here, we generate transcriptomes metabolites from six patients with brain trauma surgical samples. The resulting marker gene, which highly replicable across analysis methods, sequencing technologies, modalities, comprehensive metabolic changes human injured brains. atlas includes an area lipid peroxidation that resembles neurons We further discover imbalanced myo-inositol phosphate related markers. Our highlight complex transcriptomic regulation alterations will directly enable design reagents target specific genes analysis.

Language: Английский

---

Brain organoids are new tool for drug screening of neurological diseases

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 0(0), P. 0 - 0

Published: Jan. 1, 2023

At the level of in vitro drug screening, development a phenotypic analysis system with high-content screening at core provides strong platform to support high-throughput screening. There are few systematic reports on brain organoids, as new three-dimensional model, terms model stability, key fingerprint, and schemes, particularly regarding strategies for massive numbers traditional Chinese medicine monomers. This paper reviews organoids advantages over induced neurons or cells simulated diseases. The also highlights prospects from induction criteria schemes based characteristics application system.

Language: Английский

---

Human brain organoid model of maternal immune activation identifies radial glia cells as selectively vulnerable

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(12), P. 5077 - 5089

Published: March 6, 2023

Abstract Maternal immune activation (MIA) during critical windows of gestation is correlated with long-term neurodevelopmental deficits in the offspring, including increased risk for autism spectrum disorder (ASD) humans. Interleukin 6 (IL-6) derived from gestational parent one major molecular mediators by which MIA alters developing brain. In this study, we establish a human three-dimensional (3D) vitro model treating induced pluripotent stem cell-derived dorsal forebrain organoids constitutively active form IL-6, Hyper-IL-6. We validate our showing that express machinery necessary responding to Hyper-IL-6 and activate STAT signaling upon treatment. RNA sequencing analysis reveals upregulation histocompatibility complex class I (MHCI) genes response exposure, have been implicated ASD. find small increase proportion radial glia cells after treatment through immunohistochemistry single-cell RNA-sequencing. further show are cell type highest number differentially expressed genes, leads downregulation related protein translation line mouse MIA. Additionally, identify not found models MIA, might drive species-specific responses Finally, abnormal cortical layering as consequence summary, 3D can be used study cellular mechanisms underlying disorders such

Language: Английский

---

Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 24, 2023

Abstract De novo mutations and copy number deletions in NRXN1 (2p16.3) pose a significant risk for schizophrenia (SCZ). It is unclear how impact cortical development cell type-specific manner disease background modulates these phenotypes. Here, we leveraged human pluripotent stem cell-derived forebrain organoid models carrying heterozygous isogenic SCZ patient genetic backgrounds conducted single-cell transcriptomic analysis over the course of brain from 3 weeks to 3.5 months. Intriguingly, while both similarly impacted molecular pathways associated with ubiquitin-proteasome system, alternative splicing, synaptic signaling maturing glutamatergic GABAergic neurons, SCZ- specifically perturbed developmental trajectories early neural progenitors accumulated disease-specific signatures. Using calcium imaging, found that led long-lasting changes spontaneous synchronous neuronal networks, implicating dysfunction. Our study reveals developmental-timing- cell-type-dependent actions unique contexts.

Language: Английский

---

Application of Human Brain Organoids—Opportunities and Challenges in Modeling Human Brain Development and Neurodevelopmental Diseases

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(15), P. 12528 - 12528

Published: Aug. 7, 2023

Brain organoids are three-dimensional (3D) structures derived from human pluripotent stem cells (hPSCs) that reflect early brain organization. These contain different cell types, including neurons and glia, similar to those found in the brain. Human provide unique opportunities model features of development not well-reflected animal models. Compared with traditional cultures models, offer a more accurate representation function, rendering them suitable models for neurodevelopmental diseases. In particular, patients’ have enabled researchers study diseases at stages gain better understanding disease mechanisms. Multi-brain regional assembloids allow investigation interactions between distinct regions while achieving higher level consistency molecular functional characterization. Although possess promising features, their usefulness is limited by several unresolved constraints, cellular stress, hypoxia, necrosis, lack high-fidelity maturation, circuit formation. this review, we discuss studies overcome natural limitations organoids, emphasizing importance combinations all neural such as glia (astrocyte, oligodendrocytes, microglia) vascular cells. Additionally, considering similarity developing brain, regionally patterned organoid-derived (NSCs) could serve scalable source replacement therapy. We highlight potential application therapy within field.

Language: Английский

---