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

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.

TL1A/DR3 Axis, A Key Target of TNF-a, Augments the Epithelial–Mesenchymal Transformation of Epithelial Cells in OVA-Induced Asthma

“…Migone et al reported that the sTL1A from mTL1A is cleaved by an underlying enzyme (11). The ligand TL1A binds to the receptor DR3 to promote lymphocyte co-stimulation, mucosal hyperplasia, and autoimmune inflammation (29)(30)(31). Herro et al found that TL1A promotes lung tissue fibrosis (32).…”

Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting

“…In addition, we showed the mode of action of this antisenescence mechanism by which IHH regulates oxidative stress and the mTOR pathway through 4EBP1 and p70S6K1/2 [123]. Indeed, we reported increased expression of IHH in MSCs' that may induce the immunomodulatory power after stimulation by TL1A [183]. In summary, although the role of Hedgehog pathway in MSC senescence or longevity is still incompletely understood, it is very clear that it has a considerable contribution to the process.…”

Interaction between immuno-stem dual lineages in jaw bone formation and injury repair

“…TL1A is expressed in various immune cells, such as monocytes, macrophages, dendritic cells, and T cells. The TL1A/TNFR2 axis enhances the immunomodulatory effects of stem cells by upregulating the Ihh signaling pathway ( AL-AZAB et al, 2021 ). The classical Hh signaling pathway relies on primary cilia for transduction, which is indispensable for bone development and repair.…”

“…TL1A is expressed in various immune cells, such as monocytes, macrophages, dendritic cells, and T cells. The TL1A/TNFR2 axis enhances the immunomodulatory effects of stem cells by upregulating the Ihh signaling pathway (AL-AZAB et al, 2021).…”