title: Functional RIG-I-like receptors control the survival of mesenchymal stem cells.
abstract: Because of their potent regenerative and immunomodulatory properties, mesenchymal stem cells (MSCs) have promising therapeutic benefits in clinical treatment of inflammatory and infectious diseases. Recent studies suggest that many biological activities of MSCs are largely determined by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs). However, the role of PRRs in regulating the survival of MSCs remains unknown. In the present study, we examined the viability of MSCs after stimulation of distinct PRRs. Activation of TLRs by direct addition with their respective ligands showed no significant effect on the survival of MSCs, whereas transfection with double-stranded RNA (dsRNA) resulted in marked cell death in MSCs. Transfection of dsRNA upregulated cytosolic retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), including RIG-I and melanoma differentiation-associated antigen 5 (MDA5). Moreover, transfection of dsRNA activated downstream transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB), as well as induced the expression of interferon-β (IFN-β) and pro-inflammatory cytokine interleukin 6 (IL-6) via RLR signaling. Furthermore, we found that transfection of dsRNA triggered both extrinsic and intrinsic apoptotic responses via RLRs. However, ectopic expression of RIG-I or MDA5 was not sufficient to induce apoptosis of MSCs without dsRNA transfection. Our study also revealed that IκB kinase α/β (IKKα/β) was required for RLR-mediated apoptosis in MSCs, while TANK-binding kinase 1 (TBK1)/IKKɛ served a pro-survival role. Moreover, neither overexpression of B-cell lymphoma 2 (Bcl2) nor neutralizing autocrined IFN-β reduced RLR-mediated apoptosis. In addition, autophagy was induced upon activation of RLRs, however, blocking autophagy did not rescue MSCs from the dsRNA-induced cell death. To the best of our knowledge, this is the first study to explore the role of RLRs in controlling the survival of MSCs, which may provide a clue to understand the pathogenesis of viral infection in MSCs.
authors: 1] Department of Immunology, Zhongshan School of Medicine, Institute of Human Virology, Sun Yat-sen University, Guangzhou 510080, China [2] Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors: K
authors: K
authors: Yang
authors: 1] Department of Immunology, Zhongshan School of Medicine, Institute of Human Virology, Sun Yat-sen University, Guangzhou 510080, China [2] Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors: J
authors: J
authors: Wang
authors: Center for Stem Cell Biology and Tissue Engineering, Sun Yat-sen University, Guangzhou 510080, China.
authors: A P
authors: AP
authors: Xiang
authors: 1] Department of Immunology, Zhongshan School of Medicine, Institute of Human Virology, Sun Yat-sen University, Guangzhou 510080, China [2] Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors: X
authors: X
authors: Zhan
authors: 1] Department of Immunology, Zhongshan School of Medicine, Institute of Human Virology, Sun Yat-sen University, Guangzhou 510080, China [2] Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors: Y
authors: Y
authors: Wang
authors: 1] Department of Immunology, Zhongshan School of Medicine, Institute of Human Virology, Sun Yat-sen University, Guangzhou 510080, China [2] Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors: M
authors: M
authors: Wu
authors: 1] Department of Immunology, Zhongshan School of Medicine, Institute of Human Virology, Sun Yat-sen University, Guangzhou 510080, China [2] Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China [3] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors: X
authors: X
authors: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D050838:Interferon Regulatory Factor-3; D015850:Interleukin-6; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D016899:Interferon-beta; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1