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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 2021년 14권 1호 p.58 ~ 73
Al-Azab Mahmoud, Walana Williams, Wei Jing, Li Weiping, Tang Yawei, Wei Xiaoqing, Almoiliqy Marwan, Shopit Abdullah, Abbas Elrayah Eltahir, Adlat Salah, Awsh Mohammed, Li Xia, Wang Bing,
소속 상세정보
 ( Al-Azab Mahmoud ) - Dalian Medical University College of Basic Medical Sciences Department of Immunology
 ( Walana Williams ) - Dalian Medical University College of Basic Medical Sciences Department of Immunology
 ( Wei Jing ) - Dalian Medical University College of Basic Medical Sciences Department of Immunology
 ( Li Weiping ) - Dalian Medical University College of Basic Medical Sciences Department of Immunology
 ( Tang Yawei ) - Dalian Medical University College of Basic Medical Sciences Department of Immunology
 ( Wei Xiaoqing ) - Dalian Medical University College of Basic Medical Sciences Molecular Medicine Laboratory
 ( Almoiliqy Marwan ) - Dalian Medical University College of Pharmacy Department of Pharmacology
 ( Shopit Abdullah ) - Dalian Medical University College of Pharmacy Department of Pharmacology
 ( Abbas Elrayah Eltahir ) - Dalian Medical University College of Basic Medical Sciences Microbiology Laboratory
 ( Adlat Salah ) - Northeast Normal University School of Life Sciences
 ( Awsh Mohammed ) - Dalian Medical University College of Pharmacy Department of Pharmacology
 ( Li Xia ) - Dalian Medical University College of Basic Medical Sciences Department of Immunology
 ( Wang Bing ) - Dalian Medical University College of Basic Medical Sciences Department of Immunology

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.

키워드

Bone marrow-derived mesenchymal stem cells; Tumor necrosis factor-like ligand 1A; TNF-receptor 2; Indian hedgehog

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