Human Embryonic and Induced Pluripotent Stem Cells Express TRAIL Receptors and Can Be Sensitized to TRAIL-Induced Apoptosis

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Authors

VINARSKÝ Vladimír KŘIVÁNEK Jan RANKEL Liina NAHACKA Zuzana BÁRTA Tomáš JAROŠ Josef ANDERA Jaroslav HAMPL Aleš

Year of publication 2013
Type Article in Periodical
Magazine / Source Stem Cells and Development
MU Faculty or unit

Faculty of Medicine

Citation
Doi http://dx.doi.org/10.1089/scd.2013.0057
Field Genetics and molecular biology
Keywords TUMOR-NECROSIS-FACTOR; EXTRINSIC APOPTOSIS; MEDIATED APOPTOSIS; SELF-RENEWAL; DNA-DAMAGE; DEATH; CASPASE-8; SURVIVAL; STRESS; ACTIVATION
Description Death ligands and their tumor necrosis factor receptor (TNFR) family receptors are the best-characterized and most efficient inducers of apoptotic signaling in somatic cells. In this study, we analyzed whether these prototypic activators of apoptosis are also expressed and able to be activated in human pluripotent stem cells. We examined human embryonic stem cells (hESC) and human-induced pluripotent stem cells (hiPSC) and found that both cell types express primarily TNF-related apoptosis-inducing ligand (TRAIL) receptors and TNFR1, but very low levels of Fas/CD95. We also found that although hESC and hiPSC contain all the proteins required for efficient induction and progression of extrinsic apoptotic signaling, they are resistant to TRAIL-induced apoptosis. However, both hESC and hiPSC can be sensitized to TRAIL-induced apoptosis by co-treatment with protein synthesis inhibitors such as the anti-leukemia drug homoharringtonine (HHT). HHT treatment led to suppression of cellular FLICE inhibitory protein (cFLIP) and Mcl-1 expression and, in combination with TRAIL, enhanced processing of caspase-8 and full activation of caspase-3. cFLIP likely represents an important regulatory node, as its shRNA-mediated down-regulation significantly sensitized hESC to TRAIL-induced apoptosis. Thus, we provide the first evidence that, irrespective of their origin, human pluripotent stem cells express canonical components of the extrinsic apoptotic system and on stress can activate death receptor-mediated apoptosis.
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