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, Virenkumar A.; Crerar, Hamish; Mitchell, Jamie S.; Patani, Rickie

doi:10.3390/ijms22063256

Cited by 5 publications

(4 citation statements)

References 29 publications

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“…It has been shown that inhibiting telomerase in iPSCs using BIBR1532 followed by differentiation into midbrain dopaminergic neurons resulted in a manifestation of age-related phenotypes such as DNA damage, dendritic atrophy and mitochondrial perturbation ( Vera et al, 2016 ). Unfortunately, iPSCs and iPSC-derived MNs treated with BIBR1532 either did not survive, or, at low and well-tolerated concentrations, did not manifest age-related phenotypes ( Pandya et al, 2021 ). Thus, this approach might require further optimization, such as testing increasing treatment durations.…”

Section: Strategies To Differentiate Ipscs Into Aged Mnsmentioning

confidence: 99%

Progress and challenges in directing the differentiation of human iPSCs into spinal motor neurons

Bautista

Sterneckert

2023

Front. Cell Dev. Biol.

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Motor neuron (MN) diseases, including amyotrophic lateral sclerosis, progressive bulbar palsy, primary lateral sclerosis and spinal muscular atrophy, cause progressive paralysis and, in many cases, death. A better understanding of the molecular mechanisms of pathogenesis is urgently needed to identify more effective therapies. However, studying MNs has been extremely difficult because they are inaccessible in the spinal cord. Induced pluripotent stem cells (iPSCs) can generate a theoretically limitless number of MNs from a specific patient, making them powerful tools for studying MN diseases. However, to reach their potential, iPSCs need to be directed to efficiently differentiate into functional MNs. Here, we review the reported differentiation protocols for spinal MNs, including induction with small molecules, expression of lineage-specific transcription factors, 2-dimensional and 3-dimensional cultures, as well as the implementation of microfluidics devices and co-cultures with other cell types, including skeletal muscle. We will summarize the advantages and disadvantages of each strategy. In addition, we will provide insights into how to address some of the remaining challenges, including reproducibly obtaining mature and aged MNs.

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Section: Strategies To Differentiate Ipscs Into Aged Mnsmentioning

confidence: 99%

Progress and challenges in directing the differentiation of human iPSCs into spinal motor neurons

Bautista

Sterneckert

2023

Front. Cell Dev. Biol.

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“…Nevertheless, it is important to state that the action of BIBR1532 is found to cause a severe toxic effect in various cell types. There is also evidence to indicate that in low, non-toxic doses, BIBR1532 is not effective against telomerase activity ( 15 ). However, a detailed understanding of the molecular basis of BIBR1532 inhibition will require the crystal structure analysis of the telomerase-inhibitor complex ( 16 ).…”

Section: Resultsmentioning

confidence: 99%

Τelomerase inhibitors and activators in aging and cancer: A systematic review

et al. 2022

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The main aim of the present systematic review was to summarize the most frequently used telomerase regulators with an impact on aging and cancer that are referred to in in vitro and in vivo studies. For this purpose, a systematic review of the available literature on telomerase regulators referred to in articles from PubMed and Scopus libraries published from 2002 to 2021 and in accordance with PriSMa 2020 criteria, was conducted. articles were included if they met the following criteria: They referred to telomerase modulators in aging and in cancer and were in vitro and/or in vivo studies, while studies that did not provide sufficient data or studies not written in english were excluded. in the present systematic review, 54 publications were included, of which 29 were full-text published studies, 11 were full-text reviews, 10 structure-based design studies and 4 abstracts are reported in this review. Telomerase regulators were then categorized as synthetic direct telomerase inhibitors, synthetic indirect telomerase inhibitors, synthetic telomerase activators, natural direct telomerase activators, natural telomerase inhibitors and natural indirect telomerase activators, according to their origin and their activity. on the whole, as demonstrated herein, telomerase regulators appear to be promising treatment agents in various age-related diseases. However, further in vivo and in vitro studies need to be performed in order to clarify the potentiality of telomerase as a therapeutic target.

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“…These neurons did indeed show age-like characteristics including increased DNA damage, mitochondrial ROS and dendrite atrophy. However, there are limitations to using small molecules to regulate telomerase activity, and another study found BIBR1532 was unable to induce telomerase inhibition in hiPSC-derived motor neurons (Pandya et al 2021 ). To our knowledge, this study presents the first genetically modified hiPSC lines with reduced telomerase activity and shortened telomeres and thus provides a unique genetic model to induce aging characteristics.…”

Section: Discussionmentioning

confidence: 99%

Telomere shortening induces aging-associated phenotypes in hiPSC-derived neurons and astrocytes

Harley,

Santosa,

et al. 2023

Biogerontology

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Telomere shortening is a well-established hallmark of cellular aging. Telomerase reverse transcriptase (TERT) plays a crucial role in maintaining the length of telomeres, which are specialised protective caps at the end of chromosomes. The lack of in vitro aging models, particularly for the central nervous system (CNS), has impeded progress in understanding aging and age-associated neurodegenerative diseases. In this study, we aimed to explore the possibility of inducing aging-associated features in cell types of the CNS using hiPSC (human induced pluripotent stem cell) technology. To achieve this, we utilised CRISPR/Cas9 to generate hiPSCs with a loss of telomerase function and shortened telomeres. Through directed differentiation, we generated motor neurons and astrocytes to investigate whether telomere shortening could lead to age-associated phenotypes. Our findings revealed that shortened telomeres induced age-associated characteristics in both motor neurons and astrocytes including increased cellular senescence, heightened inflammation, and elevated DNA damage. We also observed cell-type specific age-related morphology changes. Additionally, our study highlighted the fundamental role of TERT and telomere shortening in neural progenitor cell (NPC) proliferation and neuronal differentiation. This study serves as a proof of concept that telomere shortening can effectively induce aging-associated phenotypes, thereby providing a valuable tool to investigate age-related decline and neurodegenerative diseases. Graphical abstract

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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

Cited by 5 publications

References 29 publications

Progress and challenges in directing the differentiation of human iPSCs into spinal motor neurons

Progress and challenges in directing the differentiation of human iPSCs into spinal motor neurons

Τelomerase inhibitors and activators in aging and cancer: A systematic review

Telomere shortening induces aging-associated phenotypes in hiPSC-derived neurons and astrocytes

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