Toll-like Receptor–Mediated Signaling in Human Adipose-Derived Stem Cells: Implications for Immunogenicity and Immunosuppressive Potential

Abstract

Human adipose-derived stem cells (hASCs) are mesenchymal stem cells with reduced immunogenicity and the capability to modulate immune responses. These properties make hASCs of special interest as therapeutic agents in the settings of chronic inflammatory and autoimmune diseases. Exogenous and endogenous toll-like receptor (TLR) ligands have been linked with the perpetuation of inflammation in a number of chronic inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis because of the permanent exposure of the immune system to TLR-specific stimuli. Therefore, hASCs employed in therapy are potentially exposed to TLR ligands, which may result in the modulation of hASC activity and therapeutic potency. In this study, we demonstrate that hASCs possess active TLR2, TLR3, and TLR4, because activation with specific ligands resulted in induction of nuclear factor kappa B-dependent genes, such as manganese superoxide dismutase and the release of interleukin (IL)-6 and IL-8. TLR3 and TLR4 ligands increased osteogenic differentiation, but no effect on adipogenic differentiation or proliferation was observed. Moreover, we show that TLR activation does not impair the immunogenic and immunosuppressive properties of hASCs. These results may have important implications with respect to the safety and efficacy of hASC-based cell therapies.

Emerging roles for multipotent, bone marrow–derived stromal cells in host defense

“…30,31 Specifically, TLR4-and cytokine-stimulated human MSCs may protect against oxidative stress through activation of antioxidant and anti-inflammatory pathways. 32,33 With respect to effects of TLR ligation on MSCmediated immunosuppression, Lombardo et al found that TLR3 and TLR4 ligation did not affect the ability of adipose-derived stem cells (ASCs) to inhibit T-cell proliferation, nor did TLR ligation change MSC surface HLA-II and costimulatory CD80/CD86 expression. 32 However, using human BMSCs, Liotta et al found that costimulation with TLR3 and TLR4 agonists inhibited MSCmediated suppression by down-regulating Notch ligand Jagged-1.…”

“…32,33 With respect to effects of TLR ligation on MSCmediated immunosuppression, Lombardo et al found that TLR3 and TLR4 ligation did not affect the ability of adipose-derived stem cells (ASCs) to inhibit T-cell proliferation, nor did TLR ligation change MSC surface HLA-II and costimulatory CD80/CD86 expression. 32 However, using human BMSCs, Liotta et al found that costimulation with TLR3 and TLR4 agonists inhibited MSCmediated suppression by down-regulating Notch ligand Jagged-1. 34 Furthermore, TLR3 and TLR4 activation did not affect MSC induction of IDO and PGE 2 , implying that TLR ligation could restore host defense against viral infections.…”

“…In contrast, human ASCs have not been found to up-regulate TLR expression in response to TLR ligands (LPS and poly I:C) alone or in combination with IFN-␥. 32 However, further testing is required before concluding that stromal-cell source associates with distinct TLR responses. …”

“…These immunomodulatory roles and other emerging [28][29][30][31][32][34][35][36]54 Recruitment to site of infection through chemotaxis gradients 52,54,71 Phase 2: Activation of host immune response…”

The role of Toll-like receptor 3 and 4 in regulating the function of mesenchymal stem cells isolated from umbilical cord

“…Amongst these, TLR3 can recognize double-stranded RNA in viruses and TLR4 can bind to lipopolysaccharide (LPS), a component of Gram-negative bacteria (15,16). Previous studies have demonstrated that TLR3 and TLR4 increase the osteogenic differentiation of MSCs isolated from adipose tissue and bone marrow (17). TLR3 and TLR4 have also been reported to enhance the immunosuppressive properties of human bone marrow-derived MSCS (BM-MSCs) (18).…”