Int J Stem Cells.  2021 Feb;14(1):58-73. 10.15283/ijsc19121.

TL1A/TNFR2 Axis Enhances Immunoregulatory Effects of Bone Marrow Derived Mesenchymal Stem Cell by Indian Hedgehog Signaling Pathway

Affiliations
  • 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

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.

Keyword

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