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TL1A/TNFR2 Axis Enhances Immunoregulatory Effects of Bone Marrow Derived Mesenchymal Stem Cell by Indian Hedgehog Signaling Pathway
International Journal of Stem Cells
Published online October 31, 2020;  
© 2020 Korean Society for Stem Cell Research.

Mahmoud Al-Azab1,2, Williams Walana1,7, Jing Wei1, Weiping Li1, Yawei Tang1, Xiaoqing Wei3, Marwan Almoiliqy4, Abdullah Shopit4, Elrayah Eltahir Abbas5, Salah Adlat6, Mohammed Awsh4, Xia Li1, Bing Wang1

1Department of Immunology, College of Basic Medical Science, Dalian Medical University, Liaoning, China
2Department of Immunology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
3Molecular Medicine Laboratory, College of Basic Medical Science, Dalian Medical University, Liaoning, China
4Department of Pharmacology, College of Pharmacy, Dalian Medical University, Liaoning, China
5Microbiology Laboratory, College of Basic Medical Science, Dalian Medical University, Liaoning, China
6Key Laboratory of Molecular Epigenetics of MOE, School of Life Science, Northeast Normal University, Changchun, China
7Department of Clinical Microbiology, School of Medicine and Health Sciences, University for Development Studies, Tamale, Ghana
Correspondence to: Bing Wang
Department of Immunology, College of Basic Medical Science, Dalian Medical University, Lvshun South Road, Dalian 116044, China
Tel: +86-411-86110294, E-mail: wbing79@126.com
Co-Correspondence to Xia Li
Department of Immunology, College of Basic Medical Science, Dalian Medical University, Lvshun South Road, Dalian 116044, China
Tel: +86-411-86110346, E-mail: lixia0416@dlmedu.edu.cn
Received October 2, 2019; Revised September 11, 2020; Accepted September 16, 2020.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background and Objectives: The immunomodulatory potential of mesenchymal stem cells (MSCs) can be regulated by a variety of molecules, especially cytokines. The inflammatory cytokine, TNF-like ligand 1A (TL1A), has been reported as an inflammation stimulator in multiple autoimmune diseases. Here, we studied the effects of TL1A/TNF-receptor 2 (TNFR2) pathway on the therapeutic potency of bone marrow-derived MSCs (BMSCs).
Methods and Results: BMSCs, fibroblast-like synoviocytes (FLSs), and H9 and jurkat human T lymphocytes were used in this study. BMSCs paracrine activities, differentiation, proliferation, and migration were investigated after stimulation with TL1A, and intervened with anti-TNFR2. Additionally, the effects of TL1A on BMSCs therapeutic potency were evaluated by treating RA-FLSs, and H9 and jurkat T cells with TL1A-stimulated BMSCs conditioned medium (CM). Indian hedgehog (IHH) involvement was determined by gene silencing and treatment by recombinant IHH (rIHH). TL1A induced BMSCs stemness-related genes, COX-2, IL-6, IDO, TGF-β and HGF through TNFR2. Also, TL1A corrected biased differentiation and increased proliferation, and migration through TNFR2. Meanwhile, CM of TL1A-stimulated BMSCs decreased the inflammatory markers of RA-FLSs and T cells. Moreover, TL1A-stimulated BMSCs experienced IHH up-regulation coupled with NF-κB and STAT3 signaling up-regulation, while p53 and oxidative stress were down-regulated. Furthermore, treatment of BMSCs by rIHH increased their anti-inflammatory effects. More importantly, knockdown of IHH decreased the ability of TL1A-stimulated BMSCs to alleviating the inflammation in RA-FLSs and T cells.
Conclusions: This study reports the effects of TL1A/TNFR2 pathway on the biological behaviors and therapeutic potency of BMSCs through IHH. These findings could introduce novel procedures to increase the stemness of MSCs in cellular therapy.
Keywords : Bone marrow-derived mesenchymal stem cells, Tumor necrosis factor-like ligand 1A, TNF-receptor 2, Indian hedgehog


November 2020, 13 (3)