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

Overview

Journal Stem Cells Dev

Date 2013 Jun 29

PMID 23806100

Citations 5

Authors

Vladimir Vinarsky

Jan Krivanek

Liina Rankel

Zuzana Nahacka

Tomas Barta

Josef Jaros

Ladislav Andera

Ales Hampl

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Homoharringtonine: mechanisms, clinical applications and research progress.

Wang W, He L, Lin T, Xiang F, Wu Y, Zhou F Front Oncol. 2025; 15:1522273.

PMID: 39949739 PMC: 11821653. DOI: 10.3389/fonc.2025.1522273.

Cross-Species RNA-Seq Study Comparing Transcriptomes of Enriched Osteocyte Populations in the Tibia and Skull.

Wang N, Niger C, Li N, Richards G, Skerry T Front Endocrinol (Lausanne). 2020; 11:581002.

PMID: 33071985 PMC: 7543096. DOI: 10.3389/fendo.2020.581002.

Human Embryonic Stem Cells Acquire Responsiveness to TRAIL upon Exposure to Cisplatin.

Peskova L, Vinarsky V, Barta T, Hampl A Stem Cells Int. 2019; 2019:4279481.

PMID: 30805008 PMC: 6360567. DOI: 10.1155/2019/4279481.

Molecular and epigenetic regulatory mechanisms of normal stem cell radiosensitivity.

Fabbrizi M, Warshowsky K, Zobel C, Hallahan D, Sharma G Cell Death Discov. 2018; 4:117.

PMID: 30588339 PMC: 6299079. DOI: 10.1038/s41420-018-0132-8.

Mechanistic Analysis of Physicochemical Cues in Promoting Human Pluripotent Stem Cell Self-Renewal and Metabolism.

Hai N, Shin D, Bi H, Ye K, Jin S Int J Mol Sci. 2018; 19(11).

PMID: 30400347 PMC: 6275035. DOI: 10.3390/ijms19113459.

References

Kim S, Kim B, Shim J, Gil J, Yoon Y, Kim J . Nonylphenol and octylphenol-induced apoptosis in human embryonic stem cells is related to Fas-Fas ligand pathway. Toxicol Sci. 2006; 94(2):310-21. DOI: 10.1093/toxsci/kfl114. View

Ardehali R, Inlay M, Ali S, Tang C, Drukker M, Weissman I . Overexpression of BCL2 enhances survival of human embryonic stem cells during stress and obviates the requirement for serum factors. Proc Natl Acad Sci U S A. 2011; 108(8):3282-7. PMC: 3044421. DOI: 10.1073/pnas.1019047108. View

Wuu Y, Pampfer S, Vanderheyden I, Lee K, de Hertogh R . Impact of tumor necrosis factor alpha on mouse embryonic stem cells. Biol Reprod. 1998; 58(6):1416-24. DOI: 10.1095/biolreprod58.6.1416. View

Kaufmann T, Strasser A, Jost P . Fas death receptor signalling: roles of Bid and XIAP. Cell Death Differ. 2011; 19(1):42-50. PMC: 3252833. DOI: 10.1038/cdd.2011.121. View

Barta T, Vinarsky V, Holubcova Z, Dolezalova D, Verner J, Pospisilova S . Human embryonic stem cells are capable of executing G1/S checkpoint activation. Stem Cells. 2010; 28(7):1143-52. DOI: 10.1002/stem.451. View

Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V . Inhibition of death receptor signals by cellular FLIP. Nature. 1997; 388(6638):190-5. DOI: 10.1038/40657. View

Grosse-Wilde A, Voloshanenko O, Bailey S, Longton G, Schaefer U, Csernok A . TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development. J Clin Invest. 2007; 118(1):100-10. PMC: 2129237. DOI: 10.1172/JCI33061. View

Desmarais J, Hoffmann M, Bingham G, Gagou M, Meuth M, Andrews P . Human embryonic stem cells fail to activate CHK1 and commit to apoptosis in response to DNA replication stress. Stem Cells. 2012; 30(7):1385-93. DOI: 10.1002/stem.1117. View

Gonzalvez F, Lawrence D, Yang B, Yee S, Pitti R, Marsters S . TRAF2 Sets a threshold for extrinsic apoptosis by tagging caspase-8 with a ubiquitin shutoff timer. Mol Cell. 2012; 48(6):888-99. DOI: 10.1016/j.molcel.2012.09.031. View

10.

Horova V, Hradilova N, Jelinkova I, Koc M, Svadlenka J, Brazina J . Inhibition of vacuolar ATPase attenuates the TRAIL-induced activation of caspase-8 and modulates the trafficking of TRAIL receptosomes. FEBS J. 2013; 280(14):3436-50. DOI: 10.1111/febs.12347. View

11.

Wang X, Lin G, Martins-Taylor K, Zeng H, Xu R . Inhibition of caspase-mediated anoikis is critical for basic fibroblast growth factor-sustained culture of human pluripotent stem cells. J Biol Chem. 2009; 284(49):34054-64. PMC: 2797176. DOI: 10.1074/jbc.M109.052290. View

12.

Dolezalova D, Mraz M, Barta T, Plevova K, Vinarsky V, Holubcova Z . MicroRNAs regulate p21(Waf1/Cip1) protein expression and the DNA damage response in human embryonic stem cells. Stem Cells. 2012; 30(7):1362-72. DOI: 10.1002/stem.1108. View

13.

Golks A, Brenner D, Fritsch C, Krammer P, Lavrik I . c-FLIPR, a new regulator of death receptor-induced apoptosis. J Biol Chem. 2005; 280(15):14507-13. DOI: 10.1074/jbc.M414425200. View

14.

Zampetaki A, Zeng L, Xiao Q, Margariti A, Hu Y, Xu Q . Lacking cytokine production in ES cells and ES-cell-derived vascular cells stimulated by TNF-alpha is rescued by HDAC inhibitor trichostatin A. Am J Physiol Cell Physiol. 2007; 293(4):C1226-38. DOI: 10.1152/ajpcell.00152.2007. View

15.

Zou G, Leon A, Verge V, Hirsch F, Milliez J . Fas-mediated apoptosis of mouse embryo stem cells: its role during embryonic development. Am J Reprod Immunol. 2000; 43(4):240-8. DOI: 10.1111/j.8755-8920.2000.430409.x. View

16.

Bai H, Chen K, Gao Y, Arzigian M, Xie Y, Malcosky C . Bcl-xL enhances single-cell survival and expansion of human embryonic stem cells without affecting self-renewal. Stem Cell Res. 2011; 8(1):26-37. PMC: 3222876. DOI: 10.1016/j.scr.2011.08.002. View

17.

Lavrik I, Krammer P . Regulation of CD95/Fas signaling at the DISC. Cell Death Differ. 2011; 19(1):36-41. PMC: 3252827. DOI: 10.1038/cdd.2011.155. View

18.

Aggarwal B, Gupta S, Kim J . Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood. 2011; 119(3):651-65. PMC: 3265196. DOI: 10.1182/blood-2011-04-325225. View

19.

Dickens L, Powley I, Hughes M, MacFarlane M . The 'complexities' of life and death: death receptor signalling platforms. Exp Cell Res. 2012; 318(11):1269-77. DOI: 10.1016/j.yexcr.2012.04.005. View

20.

Blum B, Bar-Nur O, Golan-Lev T, Benvenisty N . The anti-apoptotic gene survivin contributes to teratoma formation by human embryonic stem cells. Nat Biotechnol. 2009; 27(3):281-7. DOI: 10.1038/nbt.1527. View