scholarly journals Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology

2021 ◽  
Author(s):  
Kornélia Szebényi ◽  
Léa M. D. Wenger ◽  
Yu Sun ◽  
Alexander W. E. Dunn ◽  
Colleen A. Limegrover ◽  
...  
Keyword(s):  
Pluripotent Stem Cells ◽  
Patient Specific ◽  
Therapeutic Approaches ◽  
Biological Assays ◽  
Nuclear Pyknosis ◽  
Rapid Cognitive Decline ◽  
Brain Organoid ◽  
Induced Pluripotent ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

AbstractAmyotrophic lateral sclerosis overlapping with frontotemporal dementia (ALS/FTD) is a fatal and currently untreatable disease characterized by rapid cognitive decline and paralysis. Elucidating initial cellular pathologies is central to therapeutic target development, but obtaining samples from presymptomatic patients is not feasible. Here, we report the development of a cerebral organoid slice model derived from human induced pluripotent stem cells (iPSCs) that recapitulates mature cortical architecture and displays early molecular pathology of C9ORF72 ALS/FTD. Using a combination of single-cell RNA sequencing and biological assays, we reveal distinct transcriptional, proteostasis and DNA repair disturbances in astroglia and neurons. We show that astroglia display increased levels of the autophagy signaling protein P62 and that deep layer neurons accumulate dipeptide repeat protein poly(GA), DNA damage and undergo nuclear pyknosis that could be pharmacologically rescued by GSK2606414. Thus, patient-specific iPSC-derived cortical organoid slice cultures are a reproducible translational platform to investigate preclinical ALS/FTD mechanisms as well as novel therapeutic approaches.

scholarly journals Patient-Specific Induced Pluripotent Stem Cells for SOD1-Associated Amyotrophic Lateral Sclerosis Pathogenesis Studies

Acta Naturae ◽  
2014 ◽  
Vol 6 (1) ◽  
pp. 54-60 ◽  
Author(s):  
I. V. Chestkov ◽  
E. A. Vasilieva ◽  
S. N. Illarioshkin ◽  
M. A. Lagarkova ◽  
S. L. Kiselev
Keyword(s):  
Stem Cells ◽  
Amyotrophic Lateral Sclerosis ◽  
Induced Pluripotent Stem Cells ◽  
Motor Neurons ◽  
Pluripotent Stem Cells ◽  
Ips Cells ◽  
The Body ◽  
Patient Specific ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

The genetic reprogramming technology allows one to generate pluripotent stem cells for individual patients. These cells, called induced pluripotent stem cells (iPSCs), can be an unlimited source of specialized cell types for the body. Thus, autologous somatic cell replacement therapy becomes possible, as well as the generation of in vitro cell models for studying the mechanisms of disease pathogenesis and drug discovery. Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder that leads to a loss of upper and lower motor neurons. About 10% of cases are genetically inherited, and the most common familial form of ALS is associated with mutations in the SOD1 gene. We used the reprogramming technology to generate induced pluripotent stem cells with patients with familial ALS. Patient-specific iPS cells were obtained by both integration and transgene-free delivery methods of reprogramming transcription factors. These iPS cells have the properties of pluripotent cells and are capable of direct differentiation into motor neurons.

scholarly journals Advances in Patient-Specific Induced Pluripotent Stem Cells Shed Light on Drug Discovery for Amyotrophic Lateral Sclerosis

2018 ◽  
Vol 27 (9) ◽  
pp. 1301-1312 ◽  
Author(s):  
Jui-Hao Lee ◽  
Jen-Wei Liu ◽  
Shinn-Zong Lin ◽  
Horng-Jyh Harn ◽  
Tzyy-Wen Chiou
Keyword(s):  
Stem Cells ◽  
Amyotrophic Lateral Sclerosis ◽  
Induced Pluripotent Stem Cells ◽  
Motor Neurons ◽  
Pluripotent Stem Cells ◽  
Neurological Diseases ◽  
New Drugs ◽  
Patient Specific ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

Induced pluripotent stem cells (iPSCs), which are generated through reprogramming adult somatic cells by expressing specific transcription factors, can differentiate into derivatives of the three embryonic germ layers and accelerate rapid advances in stem cell research. Neurological diseases such as amyotrophic lateral sclerosis (ALS) have benefited enormously from iPSC technology. This approach can be particularly important for creating iPSCs from patients with familial or sporadic forms of ALS. Motor neurons differentiated from the ALS-patient-derived iPSC can help to determine the relationship between cellular phenotype and genotype. Patient-derived iPSCs facilitate the development of new drugs and/or drug screening for ALS treatment and allow the exploration of the possible mechanism of ALS disease. In this article, we reviewed ALS-patient-specific iPSCs with various genetic mutations, progress in drug development for ALS disease, functional assays showing the differentiation of iPSCs into mature motor neurons, and promising biomarkers in ALS patients for the evaluation of drug candidates.

scholarly journals Temporal mechanisms of myogenic specification in human induced pluripotent stem cells

2021 ◽  
Vol 7 (12) ◽  
pp. eabf7412
Author(s):  
P. Nayak ◽  
A. Colas ◽  
M. Mercola ◽  
S. Varghese ◽  
S. Subramaniam
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Patient Specific ◽  
Cellular Processes ◽  
Transcriptional Cofactors ◽  
Extracellular Matrix Components ◽  
Cell Subpopulations ◽  
Longitudinal Comparison ◽  
Induced Pluripotent

Understanding the mechanisms of myogenesis in human induced pluripotent stem cells (hiPSCs) is a prerequisite to achieving patient-specific therapy for diseases of skeletal muscle. hiPSCs of different origin show distinctive kinetics and ability to differentiate into myocytes. To address the unique cellular and temporal context of hiPSC differentiation, we perform a longitudinal comparison of the transcriptomic profiles of three hiPSC lines that display differential myogenic specification, one robust and two blunted. We detail temporal differences in mechanisms that lead to robust myogenic specification. We show gene expression signatures of putative cell subpopulations and extracellular matrix components that may support myogenesis. Furthermore, we show that targeted knockdown of ZIC3 at the outset of differentiation leads to improved myogenic specification in blunted hiPSC lines. Our study suggests that β-catenin transcriptional cofactors mediate cross-talk between multiple cellular processes and exogenous cues to facilitate specification of hiPSCs to mesoderm lineage, leading to robust myogenesis.

scholarly journals The Promise of Human Induced Pluripotent Stem Cells in Dental Research

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Thekkeparambil Chandrabose Srijaya ◽  
Padmaja Jayaprasad Pradeep ◽  
Rosnah Binti Zain ◽  
Sabri Musa ◽  
Noor Hayaty Abu Kasim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Disease Modeling ◽  
Patient Specific ◽  
Dental Research ◽  
Cell Based Therapy ◽  
Induced Pluripotent ◽  
Disease Specific

Induced pluripotent stem cell-based therapy for treating genetic disorders has become an interesting field of research in recent years. However, there is a paucity of information regarding the applicability of induced pluripotent stem cells in dental research. Recent advances in the use of induced pluripotent stem cells have the potential for developing disease-specific iPSC linesin vitrofrom patients. Indeed, this has provided a perfect cell source for disease modeling and a better understanding of genetic aberrations, pathogenicity, and drug screening. In this paper, we will summarize the recent progress of the disease-specific iPSC development for various human diseases and try to evaluate the possibility of application of iPS technology in dentistry, including its capacity for reprogramming some genetic orodental diseases. In addition to the easy availability and suitability of dental stem cells, the approach of generating patient-specific pluripotent stem cells will undoubtedly benefit patients suffering from orodental disorders.

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