Generation of two isogenic iPSC lines with either a heterozygous or a homozygous E280A mutation in the PSEN1 gene

Frederiksen, Henriette R.; Holst, Bjørn; Mau-Holzmann, Ulrike A.; Freude, Kristine; Schmid, Benjamin

doi:10.1016/j.scr.2019.101403

Cited by 17 publications

(11 citation statements)

References 4 publications

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“…The hiPSC cell line used in this study is not listed as a commonly misidentified cell line and it was not further characterized in‐house as it is a well‐characterized cell line (https://ebisc.org/BIONi010-C). The hiPSC cell line is derived from a skin biopsy from a healthy person where specific pathogenic mutations in the APP or presenilin‐1 ( PSEN‐1 ) gene were introduced by CRISPR‐Cas9, and has been previously characterized (Frederiksen, Holst, Mau‐Holzmann, et al., 2019; Frederiksen, Holst, Ramakrishna, et al., 2019). These hiPSC lines carry APOE3/4 alleles (https://ebisc.org/BIONi010-C), in addition, the APP cell line contains a heterozygous KM670/671NL mutation, and the PSEN‐1 cell line contains a homozygous E280A mutation (Frederiksen, Holst, Mau‐Holzmann, et al., 2019).…”

Section: Methodsmentioning

confidence: 99%

“…org/ BIONi 010-C). The hiPSC cell line is derived from a skin biopsy from a healthy person where specific pathogenic mutations in the APP or presenilin-1 (PSEN-1) gene were introduced by CRISPR-Cas9, and has been previously characterized (Frederiksen, Holst, Mau-Holzmann, et al, 2019;Frederiksen, Holst, Ramakrishna, et al, 2019).…”

Section: Cell Linesmentioning

confidence: 99%

“…These hiPSC lines carry APOE3/4 alleles (ebisc. org/ BIONi 010-C), in addition, the APP cell line contains a heterozygous KM670/671NL mutation, and the PSEN-1 cell line contains a homozygous E280A mutation (Frederiksen, Holst, Mau-Holzmann, et al, 2019). These mutations are hallmarks of familial forms of early-onset AD.…”

Section: Cell Linesmentioning

confidence: 99%

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Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC‐derived models of Alzheimer's disease

Salcedo,

Pozo Garcia,

García‐Adán

et al. 2023

Journal of Neurochemistry

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Glutamate recycling between neurons and astrocytes is essential to maintain neurotransmitter homeostasis. Disturbances in glutamate homeostasis, resulting in excitotoxicity and neuronal death, have been described as a potential mechanism in Alzheimer's disease (AD) pathophysiology. However, glutamate neurotransmitter metabolism in different human brain cells, particularly astrocytes, has been poorly investigated at the early stages of AD. We sought to investigate glucose and glutamate metabolism in AD by employing human induced pluripotent stem cell (hiPSC)‐derived astrocytes and neurons carrying mutations in the amyloid precursor protein (APP) or presenilin‐1 (PSEN‐1) gene as found in familial types of AD (fAD). Methods such as live‐cell bioenergetics and metabolic mapping using [13C]‐enriched substrates were used to examine metabolism in the early stages of AD. Our results revealed greater glycolysis and glucose oxidative metabolism in astrocytes and neurons with APP or PSEN‐1 mutations, accompanied by an elevated glutamate synthesis compared to control WT cells. Astrocytes with APP or PSEN‐1 mutations exhibited reduced expression of the excitatory amino acid transporter 2 (EAAT2), and glutamine uptake increased in mutated neurons, with enhanced glutamate release specifically in neurons with a PSEN‐1 mutation. These results demonstrate a hypermetabolic phenotype in astrocytes with fAD mutations possibly linked to toxic glutamate accumulation. Our findings further identify metabolic imbalances that may occur in the early phases of AD pathophysiology.

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Section: Methodsmentioning

confidence: 99%

Section: Cell Linesmentioning

confidence: 99%

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Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC‐derived models of Alzheimer's disease

Salcedo,

Pozo Garcia,

García‐Adán

et al. 2023

Journal of Neurochemistry

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“…If the disease phenotype is mutation dependent all cellular disease phenotypes should be absent and thereby recued via CRISPR-Cas9 gene editing (Lee et al, 2018 ). Another option is to introduce pathogenic mutations into a “healthy” hiPSC lines to generate a cell lines that should show a phenotype similar to the patients cell lines (Frederiksen et al, 2019 ). These corrections or insertions allow for comparative studies (Zhang et al, 2017 ) (see Figure 3 ) and furthermore allow for future opportunities of patient specific therapies (Safari et al, 2020 ).…”

Section: Generating Non-immunogenic Ipscmentioning

confidence: 99%

Non-immunogenic Induced Pluripotent Stem Cells, a Promising Way Forward for Allogenic Transplantations for Neurological Disorders

et al. 2021

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Neurological disorder is a general term used for diseases affecting the function of the brain and nervous system. Those include a broad range of diseases from developmental disorders (e.g., Autism) over injury related disorders (e.g., stroke and brain tumors) to age related neurodegeneration (e.g., Alzheimer's disease), affecting up to 1 billion people worldwide. For most of those disorders, no curative treatment exists leaving symptomatic treatment as the primary mean of alleviation. Human induced pluripotent stem cells (hiPSC) in combination with animal models have been instrumental to foster our understanding of underlying disease mechanisms in the brain. Of specific interest are patient derived hiPSC which allow for targeted gene editing in the cases of known mutations. Such personalized treatment would include (1) acquisition of primary cells from the patient, (2) reprogramming of those into hiPSC via non-integrative methods, (3) corrective intervention via CRISPR-Cas9 gene editing of mutations, (4) quality control to ensure successful correction and absence of off-target effects, and (5) subsequent transplantation of hiPSC or pre-differentiated precursor cells for cell replacement therapies. This would be the ideal scenario but it is time consuming and expensive. Therefore, it would be of great benefit if transplanted hiPSC could be modulated to become invisible to the recipient's immune system, avoiding graft rejection and allowing for allogenic transplantations. This review will focus on the current status of gene editing to generate non-immunogenic hiPSC and how these cells can be used to treat neurological disorders by using cell replacement therapy. By providing an overview of current limitations and challenges in stem cell replacement therapies and the treatment of neurological disorders, this review outlines how gene editing and non-immunogenic hiPSC can contribute and pave the road for new therapeutic advances. Finally, the combination of using non-immunogenic hiPSC and in vivo animal modeling will highlight the importance of models with translational value for safety efficacy testing; before embarking on human trials.

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“…Of course, the gene editing tools used to correct a mutation can easily be used to create a mutation in an otherwise healthy control iPSC line. Several groups have used this approach to generate disease models without needing patient involvement (Paquet et al, 2016;Tidball et al, 2017;Frederiksen et al, 2019), including a recent model for LDS (Gong et al, 2020). Despite the obvious practical advantages of this strategy, we should sound a note of caution.…”

Section: Gene Editing To Create Isogenic Controlsmentioning

confidence: 99%

Aortic “Disease-in-a-Dish”: Mechanistic Insights and Drug Development Using iPSC-Based Disease Modeling

Davaapil

Shetty

Sinha

2020

Front. Cell Dev. Biol.

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Thoracic aortic diseases, whether sporadic or due to a genetic disorder such as Marfan syndrome, lack effective medical therapies, with limited translation of treatments that are highly successful in mouse models into the clinic. Patient-derived induced pluripotent stem cells (iPSCs) offer the opportunity to establish new human models of aortic diseases. Here we review the power and potential of these systems to identify cellular and molecular mechanisms underlying disease and discuss recent advances, such as gene editing, and smooth muscle cell embryonic lineage. In particular, we discuss the practical aspects of vascular smooth muscle cell derivation and characterization, and provide our personal insights into the challenges and limitations of this approach. Future applications, such as genotype-phenotype association, drug screening, and precision medicine are discussed. We propose that iPSC-derived aortic disease models could guide future clinical trials via "clinical-trials-in-a-dish", thus paving the way for new and improved therapies for patients.

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Generation of two isogenic iPSC lines with either a heterozygous or a homozygous E280A mutation in the PSEN1 gene

Cited by 17 publications

References 4 publications

Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC‐derived models of Alzheimer's disease

Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC‐derived models of Alzheimer's disease

Non-immunogenic Induced Pluripotent Stem Cells, a Promising Way Forward for Allogenic Transplantations for Neurological Disorders

Aortic “Disease-in-a-Dish”: Mechanistic Insights and Drug Development Using iPSC-Based Disease Modeling

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