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hiPS-Derived Astroglia Model Shows Temporal Transcriptomic Profile Related to Human Neural Development and Glia Competence Acquisition of a Maturing Astrocytic Identity

Astrocyte biology has a functional and cellular diversity only observed in humans. The understanding of the regulatory network governing outer radial glia (RG), responsible for the expansion of the outer subventricular zone (oSVZ), and astrocyte cellular development remains elusive, partly since relevant human material to study these features is not readily available. A human-induced pluripotent s

Identification of cell surface markers and establishment of monolayer differentiation to retinal pigment epithelial cells

In vitro differentiation of human pluripotent stem cells into functional retinal pigment epithelial (RPE) cells provides a potentially unlimited source for cell based reparative therapy of age-related macular degeneration. Although the inherent pigmentation of the RPE cells have been useful to grossly evaluate differentiation efficiency and allowed manual isolation of pigmented structures, accurat

Assembly of FN-silk with laminin-521 to integrate hPSCs into a three-dimensional culture for neural differentiation

Three-dimensional (3D) neural tissue cultures recapitulate the basic concepts during development and disease better than what can be obtained using conventional two-dimensional cultures. Here, we use a recombinant spider silk protein functionalized with a cell binding motif from fibronectin (FN-silk) in combination with a human recombinant laminin 521 (LN-521) to create a fully defined stem cell n

p53 controls genomic stability and temporal differentiation of human neural stem cells and affects neural organization in human brain organoids

In this study, we take advantage of human induced pluripotent stem (iPS) cell-derived neural stem cells and brain organoids to study the role of p53 during human brain development. We knocked down (KD) p53 in human neuroepithelial stem (NES) cells derived from iPS cells. Upon p53KD, NES cells rapidly show centrosome amplification and genomic instability. Furthermore, a reduced proliferation rate,

DNA methylation changes in Down syndrome derived neural iPSCs uncover co-dysregulation of ZNF and HOX3 families of transcription factors

BACKGROUND: Down syndrome (DS) is characterized by neurodevelopmental abnormalities caused by partial or complete trisomy of human chromosome 21 (T21). Analysis of Down syndrome brain specimens has shown global epigenetic and transcriptional changes but their interplay during early neurogenesis remains largely unknown. We differentiated induced pluripotent stem cells (iPSCs) established from two D

Oxidative DNA Damage Signalling in Neural Stem Cells in Alzheimer's Disease

The main pathological symptoms of Alzheimer's disease (AD) are β-amyloid (Aβ) lesions and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. Unfortunately, existing symptomatic therapies targeting Aβ and tau remain ineffective. In addition to these pathogenic factors, oxidative DNA damage is one of the major threats to newborn neurons. It is necessary to consider in detail w

Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy

Medulloblastoma (MB), the most frequent malignant childhood brain tumor, can arise from cellular malfunctions during hindbrain development. Here we generate humanized models for Sonic Hedgehog (SHH)-subgroup MB via MYCN overexpression in primary human hindbrain-derived neuroepithelial stem (hbNES) cells or iPSC-derived NES cells, which display a range of aggressive phenotypes upon xenografting. iP

Single-cell study of neural stem cells derived from human iPSCs reveals distinct progenitor populations with neurogenic and gliogenic potential

We used single-cell RNA sequencing (seq) on several human induced pluripotent stem (iPS) cell-derived neural stem cell (NSC) lines and one fetal brain-derived NSC line to study inherent cell type heterogeneity at proliferating neural stem cell stage and uncovered predisposed presence of neurogenic and gliogenic progenitors. We observed heterogeneity in neurogenic progenitors that differed between

Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186

The etiology of hereditary ataxia syndromes is heterogeneous, and the mechanisms underlying these disorders are often unknown. Here, we utilized exome sequencing in two siblings with progressive ataxia and muscular weakness and identified a novel homozygous splice mutation (c.3020-1G > A) in neurofascin (NFASC). In RNA extracted from fibroblasts, we showed that the mutation resulted in inframe ski

Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality

We generated human iPS derived neural stem cells and differentiated cells from healthy control individuals and an individual with autism spectrum disorder carrying bi-allelic NRXN1-alpha deletion. We investigated the expression of NRXN1-alpha during neural induction and neural differentiation and observed a pivotal role for NRXN1-alpha during early neural induction and neuronal differentiation. Si

NRXN1 Deletion and Exposure to Methylmercury Increase Astrocyte Differentiation by Different Notch-Dependent Transcriptional Mechanisms

Controversial evidence points to a possible involvement of methylmercury (MeHg) in the etiopathogenesis of autism spectrum disorders (ASD). In the present study, we used human neuroepithelial stem cells from healthy donors and from an autistic patient bearing a bi-allelic deletion in the gene encoding for NRXN1 to evaluate whether MeHg would induce cellular changes comparable to those seen in cell

KONFLIKTERNA I SKOGEN : – EN ANALYS AV REGELKONFLIKTER OCH MYNDIGHETSAGERANDE

Vi har undersökt orsaken till de pågående kon!ikterna mellan skogsägare och skogsvårdande myndigheter angående tillämpningen av artskyddsförordningen. Vi konstaterar att myndigheterna i ett internt projekt har utvecklat en tillämp-ning av artskyddsförordningen som saknar stöd i gängse rättskällor, som lagtext, förarbeten och praxis. Tillämpningen etablerades i internt framtagna riktlinjer för hand

Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions

Down syndrome (DS) or trisomy 21 (T21) is a leading genetic cause of intellectual disability. To gain insights into dynamics of molecular perturbations during neurogenesis in DS, we established a model using induced pluripotent stem cells (iPSC) with transcriptome profiles comparable to that of normal fetal brain development. When applied on iPSCs with T21, transcriptome and proteome signatures at

Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy

BACKGROUND: Mutations in mitochondrial aminoacyl tRNA synthetases form a subgroup of mitochondrial disorders often only perturbing brain function by affecting mitochondrial translation. Here we report two siblings with mitochondrial disease, due to compound heterozygous mutations in the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, presenting with severe neurological symptoms but normal

SQSTM1/p62-Directed Metabolic Reprogramming Is Essential for Normal Neurodifferentiation

Neurodegenerative disorders are an increasingly common and irreversible burden on society, often affecting the aging population, but their etiology and disease mechanisms are poorly understood. Studying monogenic neurodegenerative diseases with known genetic cause provides an opportunity to understand cellular mechanisms also affected in more complex disorders. We recently reported that loss-of-fu

The T-type Ca2+ Channel Cav3.2 Regulates Differentiation of Neural Progenitor Cells during Cortical Development via Caspase-3

Here we report that the low-voltage-dependent T-type calcium (Ca2+) channel Cav3.2, encoded by the CACNA1H gene, regulates neuronal differentiation during early embryonic brain development through activating caspase-3. At the onset of neuronal differentiation, neural progenitor cells exhibited spontaneous Ca2+ activity. This activity strongly correlated with the upregulation of CACNA1H mRNA. Cells

Generation of induced pluripotent stem cell lines from two Neuroblastoma patients carrying a germline ALK R1275Q mutation

Neuroblastoma (NB) is an embryonic tumor of the peripheral nervous system and one of the most common solid cancers in infants. Mutations in the Anaplastic lymphoma tyrosine kinase (ALK) gene are common in NB. To study the contribution of ALK mutations in NB initiation and progression, we reprogrammed fibroblasts from two related NB patients carrying germline mutations in ALK (R1275Q) using non-int

Stem cell models of schizophrenia, what have we learned and what is the potential?

Schizophrenia is a complex disorder with clinical manifestations in early adulthood. However, it may start with disruption of brain development caused by genetic or environmental factors, or both. Early deteriorating effects of genetic/environmental factors on neural development might be key to described disease causing mechanisms. Establishing cellular models with cells from affected individual u

Quick Access to Human Astrocytic Software that Drives Neuronal Hardware

Astrocytes have important functions in the brain and their deregulation may cause disease. Current ways to derive astrocytes from pluripotent stem cells are labor, time, and resource intensive, but in this issue of Stem Cell Reports, Li et al. present a faster method to produce functional astrocytes using transcription factors.

Barrier Properties and Transcriptome Expression in Human iPSC-Derived Models of the Blood-Brain Barrier

Cell-based models of the blood-brain barrier (BBB) are important for increasing the knowledge of BBB formation, degradation and brain exposure of drug substances. Human models are preferred over animal models because of interspecies differences in BBB structure and function. However, access to human primary BBB tissue is limited and has shown degeneration of BBB functions in vitro. Human induced p