Abstract
BackgroundOur laboratory and others reported that the stimulation of specific Toll-like receptors (TLRs) affects the immune modulating responses of human multipotent mesenchymal stromal cells (hMSCs). Toll-like receptors recognize “danger” signals, and their activation leads to profound cellular and systemic responses that mobilize innate and adaptive host immune cells. The danger signals that trigger TLRs are released following most tissue pathologies. Since danger signals recruit immune cells to sites of injury, we reasoned that hMSCs might be recruited in a similar way. Indeed, we found that hMSCs express several TLRs (e.g., TLR3 and TLR4), and that their migration, invasion, and secretion of immune modulating factors is drastically affected by specific TLR-agonist engagement. In particular, we noted diverse consequences on the hMSCs following stimulation of TLR3 when compared to TLR4 by our low-level, short-term TLR-priming protocol.Principal FindingsHere we extend our studies on the effect on immune modulation by specific TLR-priming of hMSCs, and based on our findings, propose a new paradigm for hMSCs that takes its cue from the monocyte literature. Specifically, that hMSCs can be polarized by downstream TLR signaling into two homogenously acting phenotypes we classify here as MSC1 and MSC2. This concept came from our observations that TLR4-primed hMSCs, or MSC1, mostly elaborate pro-inflammatory mediators, while TLR3-primed hMSCs, or MSC2, express mostly immunosuppressive ones. Additionally, allogeneic co-cultures of TLR-primed MSCs with peripheral blood mononuclear cells (PBMCs) predictably lead to suppressed T-lymphocyte activation following MSC2 co-culture, and permissive T-lymphocyte activation in co-culture with MSC1.SignificanceOur study provides an explanation to some of the conflicting reports on the net effect of TLR stimulation and its downstream consequences on the immune modulating properties of stem cells. We further suggest that MSC polarization provides a convenient way to render these heterogeneous preparations of cells more uniform while introducing a new facet to study, as well as provides an important aspect to consider for the improvement of current stem cell-based therapies.
Highlights
Multipotent mesenchymal stromal cells are readily separated from other bone marrow-derived cells by their tendency to adhere to plastic
To provide further support for the specific effects by each of these receptors, human multipotent mesenchymal stromal cells (hMSCs) were transfected with dominant negative plasmids for each of the Toll-like receptors (TLRs)-receptors, and the factors secreted were once again measured by BioPlex assay
It is evident that Toll-like receptors (TLRs) are vital in coordinating the pro-homeostatic tissue injury responses of immune cells and that of multipotent mesenchymal stromal cells (MSCs) of various origins
Summary
Multipotent mesenchymal stromal cells (formerly known as mesenchymal stem cells, MSCs) are readily separated from other bone marrow-derived cells by their tendency to adhere to plastic. MSCs differentiate into osteoblasts, chondrocytes, and adipocytes under appropriate culture conditions [1,2,3,4] They offer the advantage that they are expanded and stored ex vivo and are considered to be ‘‘immunoprivileged.’’ once harvested they can safely be infused into either autologous or allogenous hosts owing to their lack of host immune reactivity [2]. Even though there is a clear clinical benefit observed when MSCs have been used in cell-based therapy, few infused cells (0.1–1%) have been found at the target site [2,11,12] This observation has prompted investigators to suggest that the benefit observed is due to local immune modulation by these cells rather than by differentiation or replacement of the damaged target tissue by the infused stem cells [9,10,11]. We noted diverse consequences on the hMSCs following stimulation of TLR3 when compared to TLR4 by our low-level, short-term TLR-priming protocol
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