Are mesenchymal stromal cells immune cells?

Mesenchymal stromal cells (MSCs) are considered to be promising agents for the treatment of immunological disease. Although originally identified as precursor cells for mesenchymal lineages, in vitro studies have demonstrated that MSCs possess diverse immune regulatory capacities. Pre-clinical models have shown beneficial effects of MSCs in multiple immunological diseases and a number of phase 1/2 clinical trials carried out so far have reported signs of immune modulation after MSC infusion. These data indicate that MSCs play a central role in the immune response. This raises the academic question whether MSCs are immune cells or whether they are tissue precursor cells with immunoregulatory capacity. Correct understanding of the immunological properties and origin of MSCs will aid in the appropriate and safe use of the cells for clinical therapy. In this review the whole spectrum of immunological properties of MSCs is discussed with the aim of determining the position of MSCs in the immune system

Mesenchymal stem cells control alloreactive CD8(+)CD28(-) T cells

CD28/B7 co-stimulation blockade with belatacept prevents alloreactivity in kidney transplant patients. However, cells lacking CD28 are not susceptible to belatacept treatment. As CD8(+)CD28(-) T-cells have cytotoxic and pathogenic properties, we investigated whether mesenchymal stem cells (MSC) are effective in controlling these cells. In mixed lymphocyte reactions (MLR), MSC and belatacept inhibited peripheral blood mononuclear cell (PBMC) proliferation in a dose-dependent manner. MSC at MSC/effector cell ratios of 1:160 and 1:25 reduced proliferation by 388 and 922%, respectively. Belatacept concentrations of 01g/ml and 10g/ml suppressed proliferation by 207 and 806%, respectively. Both treatments in combination did not inhibit each other's function. Allostimulated CD8(+)CD28(-) T cells were able to proliferate and expressed the cytolytic and cytotoxic effector molecules granzyme B, interferon (IFN)- and tumour necrosis factor (TNF)-. While belatacept did not affect the proliferation of CD8(+)CD28(-) T cells, MSC reduced the percentage of CD28(-) T cells in the proliferating CD8(+) T cell fraction by 459% (P=0009). CD8(+)CD28(-) T cells as effector cells in MLR in the presence of CD4(+) T cell help gained CD28 expression, an effect independent of MSC. In contrast, allostimulated CD28(+) T cells did not lose CD28 expression in MLR-MSC co-culture, suggesting that MSC control pre-existing CD28(-) T cells and not newly induced CD28(-) T cells. In conclusion, alloreactive CD8(+)CD28(-) T cells that remain unaffected by belatacept treatment are inhibited by MSC. This study indicates the potential of an MSC-belatacept combination therapy to control alloreactivity

Mesenchymal Stem Cells Induce an Inflammatory Response After Intravenous Infusion

Mesenchymal stem cells (MSCs) have potent immunosuppressive effects in vitro and are considered as a therapeutic option for autoimmune disease and organ transplantation. While MSCs show beneficial effects on immune disease progression and transplant survival in animal models, the immunomodulatory mechanisms involved are largely unknown. In the present study, we show that intravenously infused C57BL/6- green fluorescent protein (GFP) MSCs home to the lungs in C57BL/6 recipient mice and induce an inflammatory response. This response was characterized by increased mRNA expression of monocyte chemoattractant protein-1 (MCP1), IL1-, and TNF- and an increase in macrophages in lung tissue 2h after MSC infusion. Simultaneously, serum levels of proinflammatory IL6, CXCL1, and MCP1 protein increased, demonstrating systemic immune activation after MSC infusion. In liver tissue, no C57BL/6-GFP MSCs were detected, but MCP1 and TNF- mRNA levels peaked 4h after MSC infusion. The expression of the anti-inflammatory cytokines TGF-, IL4, and IL10 was only marginally affected. Nevertheless, 3 days after MSC infusion, animals developed a milder inflammatory response to lipopolysaccharides. Our results suggest that the in vivo immunomodulatory effects of MSCs originate from an inflammatory response that is induced by the infusion of MSCs, which is followed by a phase of reduced immune reactivity

Mesenchymal stem cell-educated Macrophages

Mesenchymal stem cells (MSC) mediate their immunosuppressive effects via a variety of mechanisms. One of these mechanisms involves the induction of macrophages with immunomodulatory capacities. This effect of MSC may be exploited when MSC are used as a cell therapeutic product. Furthermore, MSC are resident in tissues where they may locally target infiltrating macrophages to adapt more regulatory properties. The present review discusses the interaction between MSC and macrophages, the induction of MSC-educated macrophages, how these cells position between other immune regulatory cells, and how they may be used in the clinic

No Evidence for Circulating Mesenchymal Stem Cells in Patients with Organ Injury

Mesenchymal stem cells (MSC) are present in the bone marrow, from where they are thought to migrate through the blood stream to the sites of injury. However, virtually all tissues contain resident MSC that may contribute to local regenerative and immunomodulatory processes, thereby hypothetically preempting the need for recruiting MSC through the bloodstream. Although there is some indication for circulating MSC in animal models, there is little solid evidence for the mobilization and migration of MSC in the human circulation. In the present study, we were unable to detect MSC in the blood of healthy individuals. We then searched for MSC in the blood of ten patients with end-stage renal disease, ten patients with end-stage liver disease, and in eight heart transplant patients with biopsy-proven rejection by culturing of mononuclear cells under MSC-supporting culture conditions. In none of these patient categories, MSC were identified in the blood. MSC were, however, found in the blood of a severe trauma patient with multiple fractures, suggesting that disruption of bone marrow leads to the release of MSC into the blood stream. The conclusion of this study is that MSC are not recruited into the circulation in patients with injured solid organs and during aggressive immune responses after transplantation