Abstract
Immunomodulatory properties of mesenchymal stem cells (MSC) are key components of their successful applications in clinical setting. However, treatments based on MSC immunomodulation need understanding of cell characteristics before cell transplantation. We used live-imaging to test the suitability of the MSC motility as a parameter for quick prediction of the immunomodulatory potential of human MSC in regulating the activity of stimulated peripheral blood mononuclear cells (PBMC) in vitro. Bone marrow MSC, from various donors and in vitro passages, were cultured with or without stimulated PBMC. After seven days, immunomodulation was assessed by measuring PBMC proliferation, IgG production and cytokine secretion in MSC and PBMC monocultures and co-cultures, and results were correlated to MSC motility. In co-culture, we observed that MSC successfully inhibited PBMC activity, reducing PBMC proliferation and IgG production compared to PBMC monoculture. MSC modulated PBMC to reduce the secretion of TNFα and IL-10, increase IL-6, G-CSF and MCP-1, while GM-CSF was not affected. By live-imaging tracking of cell trajectories, we observed that fast moving MSC were inhibiting more efficiently stimulated PBMC compared to slow ones. In co-culture, fast MSC were more effective in inhibiting IgG production (˜30% less IgG), and secreted higher levels of IL-10 (˜10% increase) and GM-CSF (˜20% increase) compared to slower cells. Furthermore, fast MSC in monocultures produced 2.3-fold more IL-6, 1.5-fold MCP-1 and 1.2-fold G-CSF in comparison to slower cells. In conclusion, live-imaging cell tracking allowed us to develop an indicative assay of the immune-regulatory potential of MSC prior to in vivo administration. Key Words: Human mesenchymal stem cells, Immunomodulatory potential, In vitro cell motility, Stem cell transplantation.
Highlights
Human mesenchymal stem cells (MSC) are multipotent stromal cells with the ability to undergo extensive proliferation[1,2], produce a large number of cytokines[3], and the potential to differentiate into several cell lineages, such as adipocytes, chondrocytes, myocytes and osteoblasts[4]
MSC modulated the secretion of cytokines in unstimulated peripheral blood mononuclear cells (PBMC) co-culture, resulting in a 400-fold increase of IL-6, 3fold increase of granulocyte-colony stimulating factor (G-CSF) and 5-fold increase of monocyte chemoattractant protein-1 (MCP-1) productions, compared to PBMC monoculture
IL-10 and tumor necrosis factor α (TNF-α) levels were unaffected by the MSC, granulocyte macrophage colony-stimulating factor (GM-CSF) was inhibited 1.8-fold in comparison to PBMC monoculture
Summary
Human mesenchymal stem cells (MSC) are multipotent stromal cells with the ability to undergo extensive proliferation[1,2], produce a large number of cytokines[3], and the potential to differentiate into several cell lineages, such as adipocytes, chondrocytes, myocytes and osteoblasts[4]. Clinical trials have shown the beneficial effects of MSC application in critical health conditions like myocardial infarction[5], spinal cord injuries[6] and liver cirrhosis[7] To their tissue restorative capacity, MSC showed extensive immunomodulatory effects[8] making them potentially applicable in the treatment of immune-related diseases, such as graft versus host disease[9], systemic lupus erythematosus and multiple sclerosis[10]. It was found that by producing monocyte chemoattractant protein-1 (MCP-1 or CCL2), MSC are able to inhibit IgG production of plasma cells[22,23] and induce T-cells apoptosis via the FAS liganddependent FAS pathway[24]
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