scholarly journals Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance

2022 ◽  
Vol 119 (3) ◽  
pp. e2109395119
Author(s):  
Stephanie Cerceo Page ◽  
Srinidhi Rao Sripathy ◽  
Federica Farinelli ◽  
Zengyou Ye ◽  
Yanhong Wang ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Clinical Characteristics ◽  
Interspike Interval ◽  
Clinical Status ◽  
Risk Scores ◽  
Gamma Aminobutyric Acid ◽  
Physiological Properties ◽  
Induced Pluripotent ◽  
Human Ipsc ◽  
The Relationship

Neurons derived from human induced pluripotent stem cells (hiPSCs) have been used to model basic cellular aspects of neuropsychiatric disorders, but the relationship between the emergent phenotypes and the clinical characteristics of donor individuals has been unclear. We analyzed RNA expression and indices of cellular function in hiPSC-derived neural progenitors and cortical neurons generated from 13 individuals with high polygenic risk scores (PRSs) for schizophrenia (SCZ) and a clinical diagnosis of SCZ, along with 15 neurotypical individuals with low PRS. We identified electrophysiological measures in the patient-derived neurons that implicated altered Na+ channel function, action potential interspike interval, and gamma-aminobutyric acid–ergic neurotransmission. Importantly, electrophysiological measures predicted cardinal clinical and cognitive features found in these SCZ patients. The identification of basic neuronal physiological properties related to core clinical characteristics of illness is a potentially critical step in generating leads for novel therapeutics.

scholarly journals Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance

2021 ◽  
Author(s):  
Stephanie Cerceo Page ◽  
Srinidhi Rao Sripathy ◽  
Federica Farinelli ◽  
Zengyou Ye ◽  
Yanhong Wang ◽  
...  
Keyword(s):  
Pluripotent Stem Cells ◽  
Cortical Neurons ◽  
Clinical Characteristics ◽  
Clinical Status ◽  
Risk Scores ◽  
Na Channel ◽  
Physiological Properties ◽  
Induced Pluripotent ◽  
Human Ipsc ◽  
The Relationship

Neurons derived from human induced pluripotent stem cells (hiPSCs) have been used to model basic cellular aspects of neuropsychiatric disorders, but the relationship between the emergent phenotypes and the clinical characteristics of donor individuals has been unclear. We analyzed RNA expression and indices of cellular function in hiPSC-derived neural progenitors and cortical neurons generated from 13 individuals with high polygenic risk scores (PRS) for schizophrenia and a clinical diagnosis of schizophrenia, along with 15 neurotypical individuals with low PRS. We identified electrophysiological measures associated with diagnosis that implicated altered Na+ channel function and GABA-ergic neurotransmission. Importantly, electrophysiological measures predicted cardinal clinical and cognitive features found in these schizophrenia patients. The identification of basic neuronal physiological properties related to core clinical characteristics of illness may prove useful in generating leads that enable development of novel therapeutics.

scholarly journals Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons

2020 ◽  
Author(s):  
Swetha Gowrishankar ◽  
Lila Lyons ◽  
Nisha Mohd Rafiq ◽  
Agnes Roczniak-Ferguson ◽  
Pietro De Camilli ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Cell Biology ◽  
Neuronal Cell ◽  
Induced Pluripotent Stem Cell ◽  
App Processing ◽  
Induced Pluripotent ◽  
Aβ42 Peptide ◽  
Human Ipsc ◽  
The Relationship

AbstractThe dependence of neurons on microtubule-based motors for the movement of lysosomes over long distances raises questions about adaptations that allow neurons to meet these demands. Recently, JIP3/MAPK8IP3, a neuronally enriched putative adaptor between lysosomes and motors, was identified as a critical regulator of axonal lysosome abundance. In this study, we establish a human induced pluripotent stem cell (iPSC)-derived neuron model for the investigation of axonal lysosome transport and maturation and show that loss of JIP3 results in the accumulation of axonal lysosomes and the Alzheimer’s disease-related amyloid precursor protein (APP)-derived Aβ42 peptide. We furthermore reveal an overlapping role of the homologous JIP4 gene in lysosome axonal transport. These results establish a cellular model for investigating the relationship between lysosome axonal transport and amyloidogenic APP processing and more broadly demonstrate the utility of human iPSC-derived neurons for the investigation of neuronal cell biology and pathology.

scholarly journals Functional expression of the ATP-gated P2X7 receptor in human iPSC-derived neurons and astrocytes

2021 ◽  
Author(s):  
Jaideep Kesavan ◽  
Orla Watters ◽  
Klaus Dinkel ◽  
Michael Hamacher ◽  
Jochen H.M. Prehn ◽  
...  
Keyword(s):  
Pluripotent Stem Cells ◽  
Cortical Neurons ◽  
P2x7 Receptor ◽  
Functional Expression ◽  
Extracellular Adenosine ◽  
Functional Studies ◽  
Human Neurons ◽  
Induced Pluripotent ◽  
Human Ipsc

AbstractThe P2X7 receptor (P2X7R) is a cation membrane channel activated by extracellular adenosine 5′-triphosphate. Activation of this receptor results in numerous downstream events including the modulation of neurotransmission, release of pro-inflammatory mediators, cell proliferation or cell death. While the expression of P2X7Rs is well documented on microglia and oligodendrocytes, the presence of functional P2X7Rs on neurons and astrocytes remains debated. Furthermore, to date, functional studies on the P2X7R are mostly limited to studies in cells from rodents and immortalised cell lines expressing human P2X7Rs. To assess the functional expression of P2X7Rs in human neurons and astrocytes, we differentiated human-induced pluripotent stem cells (hiPSCs) into forebrain cortical neurons that co-express FOXG1 and βIII-tubulin as well as S100 β-expressing astrocytes. Immunostaining revealed prominent punctate P2X7R staining on the soma and processes of hiPSC-derived neurons and astrocytes. In addition, our data show that stimulation with the potent nonselective P2X7R agonist BzATP induces robust calcium rises in hiPSC-derived neurons and astrocytes, which were blocked by the selective P2X7R antagonist AFC-5128. Together, our findings provide evidence for the functional expression of P2X7Rs in hiPSC-derived forebrain cortical neurons and astrocytes demonstrating that these cells offer the potential for investigating P2X7R-mediated pathophysiology and drug screening in vitro.

scholarly journals Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons

2021 ◽  
pp. mbc.E20-06-0382
Author(s):  
Swetha Gowrishankar ◽  
Lila Lyons ◽  
Nisha Mohd Rafiq ◽  
Agnes Roczniak-Ferguson ◽  
Pietro De Camilli ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Cell Biology ◽  
Neuronal Cell ◽  
Induced Pluripotent Stem Cell ◽  
App Processing ◽  
Induced Pluripotent ◽  
Aβ42 Peptide ◽  
Human Ipsc ◽  
The Relationship

The dependence of neurons on microtubule-based motors for the movement of lysosomes over long distances raises questions about adaptations that allow neurons to meet these demands. Recently, JIP3/MAPK8IP3, a neuronally enriched putative adaptor between lysosomes and motors, was identified as a critical regulator of axonal lysosome abundance. In this study, we establish a human induced pluripotent stem cell (iPSC)-derived neuron model for the investigation of axonal lysosome transport and maturation and show that loss of JIP3 results in the accumulation of axonal lysosomes and the Alzheimer's disease-related amyloid precursor protein (APP)-derived Aβ42 peptide. We furthermore reveal an overlapping role of the homologous JIP4 gene in lysosome axonal transport. These results establish a cellular model for investigating the relationship between lysosome axonal transport and amyloidogenic APP processing and more broadly demonstrate the utility of human iPSC-derived neurons for the investigation of neuronal cell biology and pathology. [Media: see text] [Media: see text] [Media: see text] [Media: see text]

scholarly journals Human iPSC-derived astrocytes transplanted into the mouse brain undergo morphological changes in response to amyloid-β plaques

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Pranav Preman ◽  
Julia TCW ◽  
Sara Calafate ◽  
An Snellinx ◽  
Maria Alfonso-Triguero ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Morphological Changes ◽  
Amyloid Β ◽  
Induced Pluripotent Stem Cell ◽  
Functional Studies ◽  
Physiological Properties ◽  
A Cell ◽  
Induced Pluripotent ◽  
Human Ipsc ◽  
Human Specific

Abstract Background Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer’s disease comes from molecular and functional studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. Results To address these challenges, we established an approach to study human astrocytes within the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains. Xenografted hiPSC-derived astrocyte progenitors differentiated into astrocytes that integrated functionally within the mouse host brain and matured in a cell-autonomous way retaining human-specific morphologies, unique features, and physiological properties. In Alzheimer´s chimeric brains, transplanted hiPSC-derived astrocytes responded to the presence of amyloid plaques undergoing morphological changes that seemed independent of the APOE allelic background. Conclusions In sum, we describe here a promising approach that consist of transplanting patient-derived and genetically modified astrocytes into the mouse brain to study human astrocyte pathophysiology in the context of Alzheimer´s disease.

Hydrocephalus in Spinal Muscular Atrophy: A Case Report and Review of the Literature

2020 ◽  
Author(s):  
Jeetendra P. Sah ◽  
Aaron W. Abrams ◽  
Geetha Chari ◽  
Craig Linden ◽  
Yaacov Anziska
Keyword(s):  
Spinal Muscular Atrophy ◽  
Clinical Characteristics ◽  
Clinical Presentation ◽  
Muscular Atrophy ◽  
Communicating Hydrocephalus ◽  
Type I ◽  
Review Of The Literature ◽  
Radiographic Findings ◽  
Comprehensive Review ◽  
The Relationship

AbstractIn this article, we reported a case of spinal muscular atrophy (SMA) type I noted to have tetraventricular hydrocephalus with Blake's pouch cyst at 8 months of age following intrathecal nusinersen therapy. The association of hydrocephalus with SMA is rarely reported in the literature. Development of hydrocephalus after intrathecal nusinersen therapy is also reported in some cases, but a cause–effect relationship is not yet established. The aim of this study was to describe the clinical characteristics of a patient with SMA type I and hydrocephalus, to review similar cases reported in the literature, and to explore the relationship between nusinersen therapy and development of hydrocephalus. The clinical presentation and radiographic findings of the patient are described and a comprehensive review of the literature was conducted. The adverse effect of communicating hydrocephalus related to nusinersen therapy is being reported and the authors suggest carefully monitoring for features of hydrocephalus developing during the course of nusinersen therapy.

Terson sign:

2020 ◽  
Vol 2 (1) ◽  
pp. 38-43
Author(s):  
Luiz Severo Bem Junior ◽  
Gustavo De Souza Andrade ◽  
Joao Ribeiro Memória Júnior ◽  
Hildo Rocha Cirne de Azevedo Filho
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Early Recognition ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Case Reports ◽  
Clinical Status ◽  
Vitreous Hemorrhage ◽  
Anterior Communicating Artery ◽  
Inclusion Criteria ◽  
Relationship Of ◽  
The Relationship

Terson's sign (TS) is classically defined as vitreous hemorrhage associated with subarachnoid hemorrhage of aneurysmal origin, being an important predictor of severity, indicating greater morbidity and mortality when compared to patients without the sign. The objective of this study is to review the relationship of Terson syndrome/Terson sign with the prognosis of aneurysmal subarachnoid hemorrhage. A search for original articles, research and case reports was performed on the PubMed, Scielo, Cochrane and ScienceDirect platform, with the following descriptors: Terson sign and subarachnoid hemorrhage. Retrospective, prospective articles and case reports published in the last 5 years and which were in accordance with the established objective and inclusion criteria were selected. Ten (10) articles were selected, in which the available results show an unfavorable prognostic relationship of TS and subarachnoid hemorrhage, because these patients had a worse clinical status assessed on the Glasgow scales ≤ 8, Hunt & Hess > III, Fisher > 3, in addition to intracranial hypertension and location of the aneurysm in the anterior communicating artery complex. The early recognition of this condition described by Albert Terson in 1900 brought an important contribution to neurosurgery, being recognized until nowadays.

The Mitochondrion-targeted Antioxidants in Kidney Disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Xinrui Li ◽  
Liang Ma ◽  
Ping Fu
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Clinical Characteristics ◽  
Kidney Diseases ◽  
Oxygen Species ◽  
Mitochondrial Targeting ◽  
Mitochondria Dysfunction ◽  
Cellular Reactive Oxygen Species ◽  
Novel Strategy ◽  
The Relationship

: Mitochondria are potent source of cellular reactive oxygen species (ROS) and are vulnerable to oxidative damage. Mitochondria dysfunction could result in adenosine triphosphate (ATP) decrease and cell death. The kidney is an ATPconsuming organ, and the relationship between mitochondrial dysfunction and renal disease has been long noted. Mitochondrial targeting is a novel strategy for kidney diseases. At present, there are several ways to target mitochondria such as the addition of a triphenylphosphonium cation, mitochondria-targeted peptides, and nanocarrier. There are also a variety of choices for the payload, such as nitroxides, quinone derivates, vitamins and so on. This review summarized chemical and also clinical characteristics of various mitochondria-targeted antioxidants and focused on their application and perspectives in kidney diseases.

scholarly journals An Efficient Method for the Differentiation of Human iPSC-Derived Endoderm toward Enterocytes and Hepatocytes

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 812
Author(s):  
Shimeng Qiu ◽  
Yaling Li ◽  
Yuki Imakura ◽  
Shinji Mima ◽  
Tadahiro Hashita ◽  
...  
Keyword(s):  
Small Intestine ◽  
Activin A ◽  
Double Positive ◽  
Differentiation Method ◽  
Drug Metabolizing Enzyme ◽  
Human Ipscs ◽  
Novel Method ◽  
Induced Pluripotent ◽  
Metabolizing Enzyme ◽  
Human Ipsc

The endoderm, differentiated from human induced pluripotent stem cells (iPSCs), can differentiate into the small intestine and liver, which are vital for drug absorption and metabolism. The development of human iPSC-derived enterocytes (HiEnts) and hepatocytes (HiHeps) has been reported. However, pharmacokinetic function-deficiency of these cells remains to be elucidated. Here, we aimed to develop an efficient differentiation method to induce endoderm formation from human iPSCs. Cells treated with activin A for 168 h expressed higher levels of endodermal genes than those treated for 72 h. Using activin A (days 0–7), CHIR99021 and PI−103 (days 0–2), and FGF2 (days 3–7), the hiPSC-derived endoderm (HiEnd) showed 97.97% CD−117 and CD−184 double-positive cells. Moreover, HiEnts derived from the human iPSC line Windy had similar or higher expression of small intestine-specific genes than adult human small intestine. Activities of the drug transporter P-glycoprotein and drug-metabolizing enzyme cytochrome P450 (CYP) 3A4/5 were confirmed. Additionally, Windy-derived HiHeps expressed higher levels of hepatocyte- and pharmacokinetics-related genes and proteins and showed higher CYP3A4/5 activity than those derived through the conventional differentiation method. Thus, using this novel method, the differentiated HiEnts and HiHeps with pharmacokinetic functions could be used for drug development.

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