Modulation of Immune Cell Responses by Human Mesenchymal Stem Cells.

Mesenchymal stem cells (hMSCs) are multipotent stem cells that have the capacity to differentiate into various lineages. These cells provide stromal support and can be utilized as a feeder layer for expansion of hematopoitic stem cells and embryonic stem cells. Furthermore, allo-transplanted MSCs are not rejected and have been shown to mediate immuno-modulatory functions in vitro. Also, MSCs have been found at the wound site at extended times. The mechanisms underlying MSC migration and immuno-modulation are still under investigation.

Aim: To understand the factors involved in human MSC (hMSC) migration and their interaction with various immune cell types.

Methods: Human MSCs were examined for the presence of cell surface receptors that may play a role in migration using quantitative RT-PCR. Next, hMSCs were co-cultured with purified immune cell types including dendritic cells (DCs), naïve T cells and NK cells. Following the co-culture, changes in the phenotype of the immune cells under activating conditions were analyzed using ELISA and functional assays.

Results: Human MSCs express Toll receptors, especially TLR4, on their cell surface. The TLR4 on hMSCs is functional as seen by a several-fold increase in IL-6 and chemokine IL-8 upon incubation with TLR4 exogenous ligand lipopolysaccharide (LPS) and the endogenous ligand, soluble hyaluronic acid (sHA). When hMSCs were incubated with activated dendritic cells, there was a >50% decrease in TNF-α secretion and a >50% increase in IL-10 secretion. When hMSCs were incubated with naïve T cells, hMSCs decreased IFN-γ secretion and increased IL-4 secretion. Decreased IFN-γ was also seen when MSCs were incubated with NK cells.

Conclusion: These results suggest that (i) hMSCs may respond to the signals generated by breakdown products of extracellular matrix (e.g. sHA) via TLR4 and assist in wound healing (ii) hMSCs immuno-modulatory effects are mediated by interacting with various immune cell types and altering their phenotypic response to a more tolerant and anti-inflammatory response.