Chronic cardiotoxicity assessment of BMS-986094, a guanosine nucleotide analogue, using human iPS cell-derived cardiomyocytes

Age-related macular degeneration (AMD) is a blinding disease for which most of the patients remain untreatable. Since the disease affects the macula at the center of the retina, a structure specific to the primate lineage, rodent models to study the pathophysiology of AMD and to develop therapies are very limited. Consequently, our understanding relies mostly on genetic studies highlighting risk alleles at many loci. We are studying the possible implication of a metabolic imbalance associated with risk alleles within the SLC16A8 gene that encodes for a retinal pigment epithelium (RPE)-specific lactate transporter MCT3 and its consequences for vision. As a first approach, we report here the deficit in transepithelial lactate transport of a rare SLC16A8 allele identified during a genome-wide association study. We produced induced pluripotent stem cells (iPSCs) from the unique patient in our cohort that carries two copies of this allele. After in vitro differentiation of the iPSCs into RPE cells and their characterization, we demonstrate that the rare allele results in the retention of intron 2 of the SLC16A8 gene leading to the absence of MCT3 protein. We show using a biochemical assay that these cells have a deficit in transepithelial lactate transport.

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Generation of nonviral integration-free human iPS cell line KISCOi001-A from normal human fibroblasts, under defined xeno-free and feeder-free conditions

Stem Cell Research ◽

10.1016/j.scr.2021.102193 ◽

2021 ◽

Vol 51 ◽

pp. 102193

Author(s):

Jose Inzunza ◽

Jonathan Arias-Fuenzalida ◽

Juan Segura-Aguilar ◽

Ivan Nalvarte ◽

Mukesh Varshney

Keyword(s):

Cell Line ◽

Human Fibroblasts ◽

Ips Cell ◽

Normal Human

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Establishment of a non-integrate iPS cell line (SDQLCHi023-A) from a patient with Xq25 microduplication syndrome carrying a 1.3 Mb hemizygote duplication at chrXq25

Stem Cell Research ◽

10.1016/j.scr.2020.102147 ◽

2020 ◽

pp. 102147

Author(s):

Xiaomeng Yang ◽

Chunhong Duan ◽

Haiyan Zhang ◽

Yue Li ◽

Jingyun Guan ◽

...

Keyword(s):

Cell Line ◽

Ips Cell

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Drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes

Journal of Pharmacological and Toxicological Methods ◽

10.1016/j.vascn.2018.01.550 ◽

2018 ◽

Vol 93 ◽

pp. 170

Author(s):

Daiju Yamazaki ◽

Takashi Kitaguchi ◽

Masakazu Ishimura ◽

Tomohiko Taniguchi ◽

Atsuhiro Yamanishi ◽

...

Keyword(s):

Risk Assessment ◽

Drug Induced ◽

Ips Cell

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Liquid chromatographic assay for the antiviral nucleotide analogue tenofovir in plasma using derivatization with chloroacetaldehyde

Journal of Chromatography B ◽

10.1016/s1570-0232(03)00225-3 ◽

2003 ◽

Vol 791 (1-2) ◽

pp. 227-233 ◽

Cited By ~ 25

Author(s):

Rolf W. Sparidans ◽

Kristel M.L. Crommentuyn ◽

Jan H.M. Schellens ◽

Jos H. Beijnen

Keyword(s):

Nucleotide Analogue ◽

Liquid Chromatographic

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iPS-Cell Technology and the Problem of Genetic Instability—Can It Ever Be Safe for Clinical Use?

Journal of Clinical Medicine ◽

10.3390/jcm8030288 ◽

2019 ◽

Vol 8 (3) ◽

pp. 288 ◽

Cited By ~ 24

Author(s):

Stephen Attwood ◽

Michael Edel

Keyword(s):

Stem Cells ◽

Pluripotent Stem Cells ◽

Embryonic Stem ◽

Great Promise ◽

Clinical Use ◽

Medicinal Products ◽

Ips Cell ◽

Factors Affecting ◽

Induced Pluripotent ◽

Stem Cell Therapeutics

The use of induced Pluripotent Stem Cells (iPSC) as a source of autologous tissues shows great promise in regenerative medicine. Nevertheless, several major challenges remain to be addressed before iPSC-derived cells can be used in therapy, and experience of their clinical use is extremely limited. In this review, the factors affecting the safe translation of iPSC to the clinic are considered, together with an account of efforts being made to overcome these issues. The review draws upon experiences with pluripotent stem-cell therapeutics, including clinical trials involving human embryonic stem cells and the widely transplanted mesenchymal stem cells. The discussion covers concerns relating to: (i) the reprogramming process; (ii) the detection and removal of incompletely differentiated and pluripotent cells from the resulting medicinal products; and (iii) genomic and epigenetic changes, and the evolutionary and selective processes occurring during culture expansion, associated with production of iPSC-therapeutics. In addition, (iv) methods for the practical culture-at-scale and standardization required for routine clinical use are considered. Finally, (v) the potential of iPSC in the treatment of human disease is evaluated in the light of what is known about the reprogramming process, the behavior of cells in culture, and the performance of iPSC in pre-clinical studies.

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The dyskerin ribonucleoprotein complex as an OCT4/SOX2 coactivator in embryonic stem cells

eLife ◽

10.7554/elife.03573 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 21

Author(s):

Yick W Fong ◽

Jaclyn J Ho ◽

Carla Inouye ◽

Robert Tjian

Keyword(s):

Stem Cell ◽

Es Cells ◽

Embryonic Stem ◽

In Vitro Transcription ◽

Specific Gene ◽

Transcriptional Level ◽

Ips Cell ◽

Ribonucleoprotein Complex ◽

Transcription System

Acquisition of pluripotency is driven largely at the transcriptional level by activators OCT4, SOX2, and NANOG that must in turn cooperate with diverse coactivators to execute stem cell-specific gene expression programs. Using a biochemically defined in vitro transcription system that mediates OCT4/SOX2 and coactivator-dependent transcription of the Nanog gene, we report the purification and identification of the dyskerin (DKC1) ribonucleoprotein complex as an OCT4/SOX2 coactivator whose activity appears to be modulated by a subset of associated small nucleolar RNAs (snoRNAs). The DKC1 complex occupies enhancers and regulates the expression of key pluripotency genes critical for self-renewal in embryonic stem (ES) cells. Depletion of DKC1 in fibroblasts significantly decreased the efficiency of induced pluripotent stem (iPS) cell generation. This study thus reveals an unanticipated transcriptional role of the DKC1 complex in stem cell maintenance and somatic cell reprogramming.

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