scholarly journals Modeling of Frontotemporal Dementia Using iPSC Technology

2020 ◽  
Vol 21 (15) ◽  
pp. 5319
Author(s):  
Minchul Kim ◽  
Hee Jin Kim ◽  
Wonyoung Koh ◽  
Ling Li ◽  
Hyohoon Heo ◽  
...  
Keyword(s):  
Cell Death ◽  
Frontotemporal Dementia ◽  
Expression Patterns ◽  
Induced Pluripotent Stem Cell ◽  
Positive Control ◽  
Temporal Lobes ◽  
Fused In Sarcoma ◽  
Cell Death Pathway ◽  
Induced Pluripotent ◽  
Related Proteins

Frontotemporal dementia (FTD) is caused by the progressive degeneration of the frontal and temporal lobes of the brain. Behavioral variant FTD (bvFTD) is the most common clinical subtype of FTD and pathological subtypes of bvFTD are known as FTD-tau, transactive response (TAR) DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS). Pathological mechanisms of bvFTD are largely unknown. In this study, we investigated the expression of pathological markers, such as p-Tau, TDP-43, and FUS, in the induced pluripotent stem-cell-derived neurons (iPSN) from two sporadic bvFTD patients and one normal subject. We also used an FTD-patient-derived iPSC-line-carrying microtubule-associated protein tau (MAPT) P301L point mutation as positive control for p-Tau expression. Staurosporine (STS) was used to induce cellular stress in order to investigate dynamic cellular responses related to the cell death pathway. As a result, the expression of active caspase-3 was highly increased in the bvFTD-iPSNs compared with control iPSNs in the STS-treated conditions. Other cell-death-related proteins, including Bcl-2-associated X protein (Bax)/Bcl-2 and cytochrome C, were also increased in the bvFTD-iPSNs. Moreover, we observed abnormal expression patterns of TDP-43 and FUS in the bvFTD-iPSNs compared with control iPSNs. We suggest that the iPSC technology might serve as a potential tool to demonstrate neurodegenerative phenotypes of bvFTD, which will be useful for studying pathological mechanisms for FTD as well as related drug screening in the future.

scholarly journals Improving Human Induced Pluripotent Stem Cell-Derived Megakaryocyte Differentiation and Platelet Production

2021 ◽  
Vol 22 (15) ◽  
pp. 8224
Author(s):  
Linda Krisch ◽  
Gabriele Brachtl ◽  
Sarah Hochmann ◽  
André Cronemberger Andrade ◽  
Michaela Oeller ◽  
...  
Keyword(s):  
Pluripotent Stem Cells ◽  
Iterative Process ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Mesoderm Induction ◽  
Related Protein ◽  
Media Composition ◽  
Platelet Production ◽  
Induced Pluripotent ◽  
Related Proteins

Several protocols exist for generating megakaryocytes (MKs) and platelets from human induced pluripotent stem cells (hiPSCs) with limited efficiency. We observed previously that mesoderm induction improved endothelial and stromal differentiation. We, therefore, hypothesized that a protocol modification prior to hemogenic endothelial cell (HEC) differentiation will improve MK progenitor (MKP) production and increase platelet output. We further asked if basic media composition affects MK maturation. In an iterative process, we first compared two HEC induction protocols. We found significantly more HECs using the modified protocol including activin A and CHIR99021, resulting in significantly increased MKs. MKs released comparable platelet amounts irrespective of media conditions. In a final validation phase, we obtained five-fold more platelets per hiPSC with the modified protocol (235 ± 84) compared to standard conditions (51 ± 15; p < 0.0001). The regenerative potency of hiPSC-derived platelets was compared to adult donor-derived platelets by profiling angiogenesis-related protein expression. Nineteen of 24 angiogenesis-related proteins were expressed equally, lower or higher in hiPSC-derived compared to adult platelets. The hiPSC-platelet’s coagulation hyporeactivity compared to adult platelets was confirmed by thromboelastometry. Further stepwise improvement of hiPSC-platelet production will, thus, permit better identification of platelet-mediated regenerative mechanisms and facilitate manufacture of sufficient amounts of functional platelets for clinical application.

Role of Mcl-1 in regulation of cell death in human induced pluripotent stem cell-derived cardiomyocytes in vitro

2018 ◽  
Vol 360 ◽  
pp. 88-98 ◽  
Author(s):  
Liang Guo ◽  
Sandy Eldridge ◽  
Michael Furniss ◽  
Jodie Mussio ◽  
Myrtle Davis
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

scholarly journals Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly

2017 ◽  
Author(s):  
Tatsiana Aneichyk ◽  
William Hendriks ◽  
Rachita Yadav ◽  
David Shin ◽  
Dadi Gao ◽  
...  
Keyword(s):  
Intron Retention ◽  
Transcriptome Assembly ◽  
Expression Patterns ◽  
Induced Pluripotent Stem Cell ◽  
The Philippines ◽  
Causal Mechanism ◽  
Altered Expression ◽  
Causal Locus ◽  
Genomic Studies ◽  
Induced Pluripotent

X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease endemic to the Philippines. We integrated genome and transcriptome assembly with induced pluripotent stem cell-based modeling to identify the XDP causal locus and potential pathogenic mechanism. Genome sequencing identified novel variation that was shared by all probands and three recombination events that narrowed the causal locus to a genomic segment including TAF1. Transcriptome assembly in neural derivative cells discovered novel TAF1 transcripts, including a truncated transcript exclusively observed in probands that involved aberrant splicing and intron retention (IR) associated with a SINE-VNTR-Alu (SVA)-type retrotransposon insertion. This IR correlated with decreased expression of the predominant TAF1 transcript and altered expression of neurodevelopmental genes; both the IR and aberrant TAF1 expression patterns were rescued by CRISPR/Cas9 excision of the SVA. These data suggest a unique genomic cause of XDP and may provide a roadmap for integrative genomic studies in other unsolved Mendelian disorders.

scholarly journals Mitochondrial dysfunction in iPSC-derived neurons of subjects with chronic mountain sickness

2018 ◽  
Vol 125 (3) ◽  
pp. 832-840 ◽  
Author(s):  
Helen Zhao ◽  
Guy Perkins ◽  
Hang Yao ◽  
David Callacondo ◽  
Otto Appenzeller ◽  
...  
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Mitochondrial Dynamics ◽  
Induced Pluripotent Stem Cell ◽  
Mitochondrial Morphology ◽  
Chronic Mountain Sickness ◽  
Atp Levels ◽  
Mountain Sickness ◽  
Induced Pluripotent

Patients with chronic mountain sickness (CMS) suffer from hypoxemia, erythrocytosis, and numerous neurologic deficits. Here we used induced pluripotent stem cell (iPSC)-derived neurons from both CMS and non-CMS subjects to study CMS neuropathology. Using transmission electron microscopy, we report that CMS neurons have a decreased mitochondrial volume density, length, and less cristae membrane surface area. Real-time PCR confirmed a decreased mitochondrial fusion gene optic atrophy 1 (OPA1) expression. Immunoblot analysis showed an accumulation of the short isoform of OPA1 (S-OPA1) in CMS neurons, which have reduced ATP levels under normoxia and increased lactate dehydrogenase (LDH) release and caspase 3 activation after hypoxia. Improving the balance between the long isoform of OPA1 and S-OPA1 in CMS neurons increased the ATP levels and attenuated LDH release under hypoxia. Our data provide initial evidence for altered mitochondrial morphology and function in CMS neurons, and reveal increased cell death under hypoxia due in part to altered mitochondrial dynamics. NEW & NOTEWORTHY Induced pluripotent stem cell-derived neurons from chronic mountain sickness (CMS) subjects have altered mitochondrial morphology and dynamics, and increased sensitivity to hypoxic stress. Modification of OPA1 can attenuate cell death after hypoxic treatment, providing evidence that altered mitochondrial dynamics play an important role in increased vulnerability under stress in CMS neurons.

scholarly journals Human Induced Pluripotent Stem Cell Models of Frontotemporal Dementia With Tau Pathology

2021 ◽  
Vol 9 ◽  
Author(s):  
Rebekka Kühn ◽  
Aayushi Mahajan ◽  
Peter Canoll ◽  
Gunnar Hargus
Keyword(s):  
Stem Cell ◽  
Neurodegenerative Diseases ◽  
Frontotemporal Dementia ◽  
Glial Cells ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
Cell Metabolism ◽  
Induced Pluripotent Stem Cell ◽  
Early Onset Dementia ◽  
Induced Pluripotent

Neurodegenerative dementias are the most common group of neurodegenerative diseases affecting more than 40 million people worldwide. One of these diseases is frontotemporal dementia (FTD), an early onset dementia and one of the leading causes of dementia in people under the age of 60. FTD is a heterogeneous group of neurodegenerative disorders with pathological accumulation of particular proteins in neurons and glial cells including the microtubule-associated protein tau, which is deposited in its hyperphosphorylated form in about half of all patients with FTD. As for other patients with dementia, there is currently no cure for patients with FTD and thus several lines of research focus on the characterization of underlying pathogenic mechanisms with the goal to identify therapeutic targets. In this review, we provide an overview of reported disease phenotypes in induced pluripotent stem cell (iPSC)-derived neurons and glial cells from patients with tau-associated FTD with the aim to highlight recent progress in this fast-moving field of iPSC disease modeling. We put a particular focus on genetic forms of the disease that are linked to mutations in the gene encoding tau and summarize mutation-associated changes in FTD patient cells related to tau splicing and tau phosphorylation, microtubule function and cell metabolism as well as calcium homeostasis and cellular stress. In addition, we discuss challenges and limitations but also opportunities using differentiated patient-derived iPSCs for disease modeling and biomedical research on neurodegenerative diseases including FTD.

scholarly journals A human iPSC-astroglia neurodevelopmental model reveals divergent transcriptomic patterns in schizophrenia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Attila Szabo ◽  
Ibrahim A. Akkouh ◽  
Matthieu Vandenberghe ◽  
Jordi Requena Osete ◽  
Timothy Hughes ◽  
...  
Keyword(s):  
Developmental Stages ◽  
Glutamate Uptake ◽  
Expression Patterns ◽  
Induced Pluripotent Stem Cell ◽  
Specific Gene ◽  
Specific Expression ◽  
Functional Changes ◽  
Neurodevelopmental Abnormalities ◽  
Induced Pluripotent

AbstractWhile neurodevelopmental abnormalities have been associated with schizophrenia (SCZ), the role of astroglia in disease pathophysiology remains poorly understood. In the present study, we used a human induced pluripotent stem cell (iPSC)-derived astrocyte model to investigate the temporal patterns of astroglia differentiation during developmental stages critical for SCZ using RNA sequencing. The model generated astrocyte-specific gene expression patterns during differentiation that corresponded well to astroglia-specific expression signatures of in vivo cortical fetal development. Using this model we identified SCZ-specific expression dynamics, and found that SCZ-associated differentially expressed genes were significantly enriched in the medial prefrontal cortex, striatum, and temporal lobe, targeting VWA5A and ADAMTS19. In addition, SCZ astrocytes displayed alterations in calcium signaling, and significantly decreased glutamate uptake and metalloproteinase activity relative to controls. These results implicate novel transcriptional dynamics in astrocyte differentiation in SCZ together with functional changes that are potentially important biological components of SCZ pathology.

scholarly journals Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects

Cell Reports ◽  
2012 ◽  
Vol 2 (5) ◽  
pp. 1471 ◽  
Author(s):  
Sandra Almeida ◽  
Zhijun Zhang ◽  
Giovanni Coppola ◽  
Wenjie Mao ◽  
Kensuke Futai ◽  
...  
Keyword(s):  
Stem Cell ◽  
Frontotemporal Dementia ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Cell Models ◽  
Induced Pluripotent ◽  
Stem Cell Models

scholarly journals Distinct Neurodegenerative Changes in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia Linked to Mutant TAU Protein

2015 ◽  
Vol 5 (1) ◽  
pp. 83-96 ◽  
Author(s):  
Marc Ehrlich ◽  
Anna-Lena Hallmann ◽  
Peter Reinhardt ◽  
Marcos J. Araúzo-Bravo ◽  
Sabrina Korr ◽  
...  
Keyword(s):  
Stem Cell ◽  
Frontotemporal Dementia ◽  
Tau Protein ◽  
Pluripotent Stem Cell ◽  
Cell Model ◽  
Induced Pluripotent Stem Cell ◽  
Stem Cell Model ◽  
Induced Pluripotent
Sign in / Sign up

Export Citation Format

Share Document