Abstract TP97: Physiological Plasma Concentrations of Atorvastatin and Simvastatin Enhance the Immunomodulatory Effects of Mesenchymal Stromal Cells on Stroke Derived Monocytes

Abstract

Background: Mesenchymal stromal cells (MSCs) are being investigated as a stroke therapy both in preclinical and clinical trials. MSCs may promote recovery through secretome release and immunomodulation. Approximately one-third of stroke patients are on statins. With cell therapy gaining momentum, we explored the effect of two statins on MSCs. Methods: Clinical grade bone marrow MSCs from 3 healthy donors at passage 2 were thawed and re-suspended in serum free media. Monocytes (Mo) were isolated from peripheral blood of healthy humans and stroke patients. MSCs and Mo were cultured alone as well as in co-culture and exposed to different doses of atorvastatin and simvastatin. At 24 and 48 hours of incubation, viability of MSCs was measured using ATP assay. 5-bromo-2’-deoxyuridine (BrdU) assay was used to measure proliferation. Media from treated MSCs was analyzed for secretomes and treated cells were analyzed for gene expression changes. Data were averaged for 3 donors. Results: Both atorvastatin and simvastatin decreased the viability and proliferation of MSCs (Fig. 1A-B), but at physiologically relevant doses both were maintained above 90%. Clinically relevant doses of both drugs decreased the secretion of TNF-α and IL-6 from MSCs upto two fold (Fig. 1C-D). IL-6 expression decreased and IL-10 expression increased dose-dependently in MSCs (data not shown). When co-cultured with Mo from control vs stroke patients, both statins at physiologically relevant doses increased VEGF release and decreased the secretion of IL-6, IL-8 and MCP-1 (Fig. 1E-H). Conclusion: Exposure of MSCs to statins can alter their immunomodulatory function. Furthermore, these effects are consistent across two commonly prescribed drugs. Our results suggest that stroke trials involving use of intravenous MSCs should consider the impact of statins on MSC function.