scholarly journals SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs

2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Peiyee Lee ◽  
Nathan T. Martin ◽  
Kotoka Nakamura ◽  
Soheila Azghadi ◽  
Mandana Amiri ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Patient Specific ◽  
Cellular Phenotypes ◽  
Derivatives Of

Actual strategies in human induced pluripotent stem cells (hiPSCs) differentiation – perspectives and challenges

2016 ◽  
Vol 52 (2) ◽  
pp. 123-136
Author(s):  
Ewelina Augustyniak ◽  
Katarzyna Kulcenty ◽  
Michał Lach ◽  
Igor Piotrowski ◽  
Wiktoria Maria Suchorska
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Embryonic Stem ◽  
Patient Specific ◽  
Human Embryos ◽  
Alternative Approaches ◽  
Induced Pluripotent ◽  
Autologous Grafts ◽  
Derivatives Of

The application of stem cells (SCs) in regenerative medicine has recently become a rapidly growing field, holding promise for combating a number of currently incurable disorders: including diabetes, neurodegenerative, retinal and cardiac diseases, as well as muscular dystrophy. The search for alternative approaches led to the development of human induced pluripotent stem cells (hiPSCs) which have unrestricted proliferative activity and pluripotency – the capacity to differentiation into derivatives of three germ layers (meso-, ecto – and endoderm). Because hiPSCs are developed from adult human cells throughout the forced expression of pluripotency factors, they are free from the ethical concerns associated with human embryonic stem cells (hESCs), that creation involves the destruction of human embryos. Moreover, the use of hiPSCs contributes to the development of personalized medicine that exploits patient-specific cells extremely useful in autologous grafts. In the present study the methods of hiPSCs differentiation into stem cell-derived neurons, cardiomyocytes, chondrocytes and osteocytes were summarized and evaluated having regard to their most important aspects.

A Patient-Specific Stem Cell Model to Investigate the Neurological Phenotype Observed in Ataxia-Telangiectasia

2017 ◽  
pp. 391-400
Author(s):  
Romal Stewart ◽  
Gautam Wali ◽  
Chris Perry ◽  
Martin F. Lavin ◽  
Francois Féron ◽  
...  
Keyword(s):  
Stem Cell ◽  
Ataxia Telangiectasia ◽  
Cell Model ◽  
Patient Specific ◽  
Neurological Phenotype ◽  
Stem Cell Model

scholarly journals Modelling Parkinson’s Disease: iPSCs towards Better Understanding of Human Pathology

2021 ◽  
Vol 11 (3) ◽  
pp. 373
Author(s):  
Sahar Avazzadeh ◽  
Jara Maria Baena ◽  
Cameron Keighron ◽  
Yajaira Feller-Sanchez ◽  
Leo R. Quinlan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Gene Mutations ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Human Pathology ◽  
Different Genetic Background ◽  
Cellular Phenotypes

Parkinson’s Disease (PD) is a chronic neurodegenerative disorder characterized by motor and non-motor symptoms, among which are bradykinesia, rigidity, tremor as well as mental symptoms such as dementia. The underlying cause of Parkinson disease is degeneration of dopaminergic neurons. It has been challenging to develop an efficient animal model to accurately represent the complex phenotypes found with PD. However, it has become possible to recapitulate the myriad of phenotypes underlying the PD pathology by using human induced pluripotent stem cell (iPSC) technology. Patient-specific iPSC-derived dopaminergic neurons are available and present an opportunity to study many aspects of the PD phenotypes in a dish. In this review, we report the available data on iPSC-derived neurons derived from PD patients with identified gene mutations. Specifically, we will report on the key phenotypes of the generated iPSC-derived neurons from PD patients with different genetic background. Furthermore, we discuss the relationship these cellular phenotypes have to PD pathology and future challenges and prospects for iPSC modelling and understanding of the pathogenesis of PD.

An iPSC-Based Model Of MDS For Phenotype-Driven Gene and Drug Discovery

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 859-859
Author(s):  
Ibrahim Boussaad ◽  
Andriana Kotini ◽  
Emily K Dolezal ◽  
Stephen Nimer ◽  
Eirini P Papapetrou
Keyword(s):  
Drug Development ◽  
High Throughput ◽  
Disease Process ◽  
Patient Specific ◽  
Dependent Manner ◽  
Hematopoietic Differentiation ◽  
Ipsc Line ◽  
Ongoing Research ◽  
Disease Study ◽  
Cellular Phenotypes

Abstract Despite past and ongoing research efforts, the pathogenetic mechanisms of MDS remain far from understood sufficiently to point to single genes or molecular pathways as putative targets for generation of better mouse models or drug development. In lack of clear targets, the manipulation of disease-associated phenotypes may at present be the best opportunity for disease study and therapeutic intervention. Furthermore, because cellular phenotypes are more proximal to molecular disease mechanisms than phenotypes seen at the level of the tissue or organism (i.e. the murine or human hematopoietic system), they may provide more sensitive and relevant readouts of the disease process. With the advent of patient-specific induced pluripotent stem cells (iPSCs), disease models based on cellular phenotypes (“disease-in-a-dish”) can now be developed and their unique properties promise to revolutionize disease study and drug development. Unlimited cell numbers of biologically relevant cells can be obtained relatively easily and cost-effectively. Here we present a new MDS model based on patient-specific iPSCs and its use in two phenotype-driven screens: (a) a focused genetic screen and (b) a high-throughput chemical screen. We have derived multiple MDS-iPSC lines with deletions of chromosomes 7q or 20q (characteristic chromosomal deletions that we are using as markers of iPSCs derived from the MDS clone) from bone marrow (BM) of 3 patients with MDS and 1 patient with sAML. We also derived isogenic karyotypically normal iPSC lines in parallel from the same BM samples. We identified two cellular phenotypes specific to the MDS-iPSCs: decreased proliferation rate and decreased potential for pan-hematopoietic differentiation and reduced clonogenic capacity of their hematopoietic progeny. These phenotypes are consistent across multiple iPSC lines from different patients and absent from their isogenic normal iPSC controls. They are reminiscent of the behavior of ex vivo cultured primary MDS BM cells and are therefore likely to be relevant to the disease process. Furthermore, they are rescued by spontaneous compensation for chr7q dosage through acquisition of an extra chr7 and recapitulated by the engineering of artificial chr7q deletions in normal iPSCs. To identify critical MDS gene(s) on chr7q, we performed a screen of 62 candidate haploinsufficient genes (with reduced expression by at least 1.5-fold in our del(7q)-iPSCs compared to their isogenic normal iPSCs) for rescue of the proliferation and/or hematopoietic differentiation phenotype. We constructed a lentiviral library of all candidate ORFs (and 14 additional alternative transcripts) linked to eGFP through a P2A peptide and each tagged with a unique 4-nt barcode sequence to its 3’ UTR. The library was packaged as a pool and transduced into two different del(7q)-iPSC lines. The cells were passaged for 16 weeks and gDNA was isolated every 2 weeks. In parallel, the cells were differentiated along the hematopoietic lineage and gDNA was isolated from CD45+ cells FACS-sorted on day 15 of differentiation. High-throughput sequencing of the barcodes identified 5 ORFs that became enriched in undifferentiated iPSCs over time (rescue of proliferation) and 4 ORFs enriched in sorted CD45+hematopoietic progenitors (rescue of hematopoietic differentiation), 2 of which overlapped. All 9 hits are being further validated in more focused screens. Second, we used the same platform for a high-throughput small molecule screen. We optimized the plating conditions and densities for a 384-well format using a luminescent cell viability assay and conducted a screen of 2000 compounds comprising known drugs, natural products, and other bioactives and chemicals, in an MDS-iPSC line (2.13) and its isogenic normal control (2.8). Primary hits were defined as compounds that enhanced the growth of the MDS-iPSC line, but not of the control normal iPSC line in a compound dose-dependent manner. 38 primary hits were retested in a dose-response survival assay in one additional MDS- (2.A1-3), one additional isogenic normal iPSC line (2.12) and one sAML iPSC line over 8 concentrations and 12 compounds were prioritized for further studies. Our data highlight the potential of this new iPSC-based model of MDS for screens to identify genes or compounds that affect cellular phenotypes by acting on previously undefined targets. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Human iPSC-Derived Hippocampal Spheroids: An Innovative Tool for Stratifying Alzheimer Disease Patient-Specific Cellular Phenotypes and Developing Therapies

2020 ◽  
Vol 15 (1) ◽  
pp. 256-273
Author(s):  
Yuriy Pomeshchik ◽  
Oxana Klementieva ◽  
Jeovanis Gil ◽  
Isak Martinsson ◽  
Marita Grønning Hansen ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Disease Patient ◽  
Patient Specific ◽  
Alzheimer Disease Patient ◽  
Innovative Tool ◽  
Cellular Phenotypes ◽  
Human Ipsc

scholarly journals Human iPSC-derived hippocampal spheroids: An innovative tool for stratifying Alzheimer disease patient-specific cellular phenotypes and developing therapies

2021 ◽  
Vol 16 (11) ◽  
pp. 2838
Author(s):  
Yuriy Pomeshchik ◽  
Oxana Klementieva ◽  
Jeovanis Gil ◽  
Isak Martinsson ◽  
Marita Grønning Hansen ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Disease Patient ◽  
Patient Specific ◽  
Alzheimer Disease Patient ◽  
Innovative Tool ◽  
Cellular Phenotypes ◽  
Human Ipsc

scholarly journals Mechanisms Underlying the Suppression of Chromosome Rearrangements by Ataxia-Telangiectasia Mutated

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1232
Author(s):  
Motohiro Yamauchi
Keyword(s):  
Ataxia Telangiectasia ◽  
Cellular Response ◽  
Chromosome Rearrangement ◽  
Autosomal Recessive Disorder ◽  
Cellular Level ◽  
Chromosome Rearrangements ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Structural Variations ◽  
Cellular Phenotypes

Chromosome rearrangements are structural variations in chromosomes, such as inversions and translocations. Chromosome rearrangements have been implicated in a variety of human diseases. Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by a broad range of clinical and cellular phenotypes. At the cellular level, one of the most prominent features of A-T cells is chromosome rearrangement, especially that in T lymphocytes. The gene that is defective in A-T is ataxia-telangiectasia mutated (ATM). The ATM protein is a serine/threonine kinase and plays a central role in the cellular response to DNA damage, particularly DNA double-strand breaks. In this review, the mechanisms by which ATM suppresses chromosome rearrangements are discussed.

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