Pluripotent Stem Cells Are Insensitive to the Cytotoxicity of TNFα and IFNγ

Overview

Journal Reproduction

Specialty Reproductive Medicine

Date 2020 Jul 23

PMID 32698161

Citations 6

Authors

Bohan Chen

Chandan Gurung

Jason Guo

Chulan Kwon

Yan-Lin Guo

Affiliations

Soon will be listed here.

Abstract

Recent studies have demonstrated that embryonic stem cells (ESCs) have an underdeveloped innate immune system, but the biological implications of this finding are poorly understood. In this study, we compared the responses of mouse ESCs (mESCs) and mESC differentiated fibroblasts (mESC-FBs) to tumor necrosis factor α (TNFα) and interferons (IFNs). Our data revealed that TNFα, IFNα, IFNβ, or IFNγ alone do not cause apparent effects on mESCs and mESC-FBs, but the combination of TNFα and IFNγ (TNFα/IFNγ) showed toxicity to mESC-FBs as indicated by cell cycle inhibition and reduced cell viability, correlating with the expression of inducible nitric oxide synthase (iNOS). However, none of these effects were observed in mESCs that were treated with TNFα/IFNγ. Furthermore, mESC-FBs, but not mESCs, are vulnerable to cytotoxicity resulting from lipopolysaccharide (LPS)-activated macrophages. The insensitivity of mESCs to cytotoxicity in all cases is correlated with their lack of responses to TNFα and IFNγ. Similar to mESCs, human ESCs (hESCs) and iPSCs (hiPSCs) do not respond to TNFα and are not susceptible to the cytotoxicity of TNFα, IFNβ, or IFNγ alone or in combination that significantly affects human foreskin fibroblast (hFBs) and Hela cells. However, unlike mESCs, hESCs and hiPSCs can respond to IFNγ, but this does not cause significant cytotoxicity in hESCs and hiPSCs. Our findings in both mouse and human PSCs together support the hypothesis that attenuated innate immune responses could be a protective mechanism that limits immunologic cytotoxicity resulting from inflammatory and immune responses.

Citing Articles

Equine Embryonic Stem Cell-Derived Tenocytes are Insensitive to a Combination of Inflammatory Cytokines and Have Distinct Molecular Responses Compared to Primary Tenocytes.

Smith E, Beaumont R, Dudhia J, Guest D Stem Cell Rev Rep. 2024; 20(4):1040-1059.

PMID: 38396222 PMC: 11087315. DOI: 10.1007/s12015-024-10693-8.

Mouse Trophoblast Cells Have Attenuated Responses to TNF-α and IFN-γ and Can Avoid Synergic Cytotoxicity of the Two Cytokines.

Fendereski M, Ming H, Jiang Z, Guo Y J Immunol. 2023; 212(2):346-354.

PMID: 38054905 PMC: 10843640. DOI: 10.4049/jimmunol.2300210.

Equine induced pluripotent stem cells are responsive to inflammatory cytokines before and after differentiation into musculoskeletal cell types.

Palomino Lago E, Jelbert E, Baird A, Lam P, Guest D In Vitro Cell Dev Biol Anim. 2023; 59(7):514-527.

PMID: 37582999 PMC: 10520172. DOI: 10.1007/s11626-023-00800-3.

Transient upregulation of IRF1 during exit from naive pluripotency confers viral protection.

Romeike M, Spach S, Huber M, Feng S, Vainorius G, Elling U EMBO Rep. 2022; 23(9):e55375.

PMID: 35852463 PMC: 9442322. DOI: 10.15252/embr.202255375.

Mouse Trophoblast Cells Can Provide IFN-Based Antiviral Protection to Embryonic Stem Cells via Paracrine Signaling.

Fendereski M, Neupane B, Nazneen F, Bai F, Guo Y J Immunol. 2022; 208(12):2761-2770.

PMID: 35649628 PMC: 9308691. DOI: 10.4049/jimmunol.2100679.

References

Drukker M, Katz G, Urbach A, Schuldiner M, Markel G, Itskovitz-Eldor J . Characterization of the expression of MHC proteins in human embryonic stem cells. Proc Natl Acad Sci U S A. 2002; 99(15):9864-9. PMC: 125045. DOI: 10.1073/pnas.142298299. View

Kim W, Lee J, Gao B, Jung M . Synergistic activation of JNK/SAPK induced by TNF-alpha and IFN-gamma: apoptosis of pancreatic beta-cells via the p53 and ROS pathway. Cell Signal. 2005; 17(12):1516-32. DOI: 10.1016/j.cellsig.2005.03.020. View

Schroder K, Hertzog P, Ravasi T, Hume D . Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2003; 75(2):163-89. DOI: 10.1189/jlb.0603252. View

Jenkins C, Roberts J, Wilson R, MacLean M, Shilito J, Walker J . Evidence of a T(H) 1 type response associated with recurrent miscarriage. Fertil Steril. 2000; 73(6):1206-8. DOI: 10.1016/s0015-0282(00)00517-3. View

Sedger L, McDermott M . TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants - past, present and future. Cytokine Growth Factor Rev. 2014; 25(4):453-72. DOI: 10.1016/j.cytogfr.2014.07.016. View

Clemens M . Interferons and apoptosis. J Interferon Cytokine Res. 2003; 23(6):277-92. DOI: 10.1089/107999003766628124. View

Takahashi S, Kobayashi S, Hiratani I . Epigenetic differences between naïve and primed pluripotent stem cells. Cell Mol Life Sci. 2017; 75(7):1191-1203. PMC: 5843680. DOI: 10.1007/s00018-017-2703-x. View

Napetschnig J, Wu H . Molecular basis of NF-κB signaling. Annu Rev Biophys. 2013; 42:443-68. PMC: 3678348. DOI: 10.1146/annurev-biophys-083012-130338. View

Song W, Lu X, Feng Q . Tumor necrosis factor-alpha induces apoptosis via inducible nitric oxide synthase in neonatal mouse cardiomyocytes. Cardiovasc Res. 2000; 45(3):595-602. DOI: 10.1016/s0008-6363(99)00395-8. View

10.

Guo Y . Utilization of different anti-viral mechanisms by mammalian embryonic stem cells and differentiated cells. Immunol Cell Biol. 2016; 95(1):17-23. PMC: 5568901. DOI: 10.1038/icb.2016.70. View

11.

Pick M, Ronen D, Yanuka O, Benvenisty N . Reprogramming of the MHC-I and its regulation by NFκB in human-induced pluripotent stem cells. Stem Cells. 2012; 30(12):2700-8. DOI: 10.1002/stem.1242. View

12.

Wang R, Wang J, Acharya D, Paul A, Bai F, Huang F . Antiviral responses in mouse embryonic stem cells: differential development of cellular mechanisms in type I interferon production and response. J Biol Chem. 2014; 289(36):25186-98. PMC: 4155682. DOI: 10.1074/jbc.M113.537746. View

13.

Guo Y, Ye J, Huang F . p38alpha MAP kinase-deficient mouse embryonic stem cells can differentiate to endothelial cells, smooth muscle cells, and neurons. Dev Dyn. 2007; 236(12):3383-92. DOI: 10.1002/dvdy.21374. View

14.

Kimura M, Haisa M, Uetsuka H, Takaoka M, Ohkawa T, Kawashima R . TNF combined with IFN-alpha accelerates NF-kappaB-mediated apoptosis through enhancement of Fas expression in colon cancer cells. Cell Death Differ. 2003; 10(6):718-28. DOI: 10.1038/sj.cdd.4401219. View

15.

Wu X, Dao Thi V, Huang Y, Billerbeck E, Saha D, Hoffmann H . Intrinsic Immunity Shapes Viral Resistance of Stem Cells. Cell. 2017; 172(3):423-438.e25. PMC: 5786493. DOI: 10.1016/j.cell.2017.11.018. View

16.

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

17.

Cameo M, Fontana V, Cameo P, Vauthay L, Kaplan J, Tesone M . Similar embryotoxic effects of sera from infertile patients and exogenous interferon-gamma on long-term in-vitro development of mouse embryos. Hum Reprod. 1999; 14(4):959-63. DOI: 10.1093/humrep/14.4.959. View

18.

Ganster R, Taylor B, Shao L, Geller D . Complex regulation of human inducible nitric oxide synthase gene transcription by Stat 1 and NF-kappa B. Proc Natl Acad Sci U S A. 2001; 98(15):8638-43. PMC: 37488. DOI: 10.1073/pnas.151239498. View

19.

Holtzman M, Morton J, Shornick L, Tyner J, OSullivan M, Antao A . Immunity, inflammation, and remodeling in the airway epithelial barrier: epithelial-viral-allergic paradigm. Physiol Rev. 2002; 82(1):19-46. DOI: 10.1152/physrev.00020.2001. View

20.

Roebuck K, Finnegan A . Regulation of intercellular adhesion molecule-1 (CD54) gene expression. J Leukoc Biol. 1999; 66(6):876-88. DOI: 10.1002/jlb.66.6.876. View