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A non-toxic concentration of telomerase inhibitor BIBR1532 fails to reduce tert expression in a feeder-free induced pluripotent stem cell model of human motor neurogenesis

Pandya, VA; Crerar, H; Mitchell, JS; Patani, R; (2021) A non-toxic concentration of telomerase inhibitor BIBR1532 fails to reduce tert expression in a feeder-free induced pluripotent stem cell model of human motor neurogenesis. International Journal of Molecular Sciences , 22 (6) , Article 3256. 10.3390/ijms22063256. Green open access

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Abstract

Several studies have shown that human induced pluripotent stem cell (iPSC)-derivatives are essentially fetal in terms of their maturational status. Inducing ageing in iPSC-motor neuron (MN) models of amyotrophic lateral sclerosis (ALS) has the potential to capture pathology with higher fidelity and consequently improve translational success. We show here that the telomerase inhibitor BIBR1532, hypothesised to recapitulate the telomere attrition hallmark of ageing in iPSC-MNs, was in fact cytotoxic to feeder-free iPSCs when used at doses previously shown to be effective in iPSCs grown on a layer of mouse embryonic fibroblasts. Toxicity in feeder-free cultures was not rescued by co-treatment with Rho Kinase (ROCK) inhibitor (Y-27632). Moreover, the highest concentration of BIBR1532 compatible with continued iPSC culture proved insufficient to induce detectable telomerase inhibition. Our data suggest that direct toxicity by BIBR1532 is the most likely cause of iPSC death observed, and that culture methods may influence enhanced toxicity. Therefore, recapitulation of ageing hallmarks in iPSC-MNs, which might reveal novel and relevant human disease targets in ALS, is not achievable in feeder-free culture through the use of this small molecule telomerase inhibitor.

Type: Article
Title: A non-toxic concentration of telomerase inhibitor BIBR1532 fails to reduce tert expression in a feeder-free induced pluripotent stem cell model of human motor neurogenesis
Open access status: An open access version is available from UCL Discovery
DOI: 10.3390/ijms22063256
Publisher version: https://doi.org/10.3390/ijms22063256
Language: English
Additional information: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Keywords: ageing; amyotrophic lateral sclerosis (ALS); telomerase; TERT; BIBR1532; induced pluripotent stem cells (iPSC); motor neurons (MNs)
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10125516
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