Reprogramming inflammatory macrophages with mesenchymal stromal cells

Abstract

Background & Aim MSCs represent approximately 25% of all cell-based clinical trials with over 1,000 registered on clinicaltrials.gov. Although the safety of MSCs is well-documented, the success in trials over the past 25 years is variable. This is likely due to the differences in the source tissue to generate MSCs, manufacturing procedures, the heterogeneity of the MSC populations, and the disease being targeted. Regardless of these differences, it is absolutely critical to understand the mechanism of action in vivo to optimize the potential of MSCs as a FDA licensed cell therapy product. Recent reports highlight that MSCs are rapidly cleared in vivo yet modulate myeloid cell populations to limit inflammation well after they are no longer detectable. Human umbilical cord tissue is readily available and a rich source of rapidly proliferating MSCs. In this study, we hypothesized that human cord tissue-derived MSCs (hCT-MSCs) can reprogram inflammatory macrophages and limit disease progression in inflammatory diseases. Methods, Results & Conclusion Multiple lines of hCT-MSCs were manufactured from donated cord tissue in the Robertson GMP laboratory within the Marcus Center for Cellular Cures (MC3). Using cell culture assays, we determined that hCT-MSC indirectly suppressed T cells by directly interacting with macrophages. Macrophages did not phagocytosis live MSCs, rather they engulfed cytoplasmic components, which down-regulated genes responsible for presenting antigens and activating T cells. Since vast amounts of information can be stored within cytoplasmic granules call processing bodies (P-bodies), we tested their role in facilitating hCT-MSCs to reprogram macrophages. hCT-MSCs contained substantially numbers of P-bodies in the cytoplasm and when we genetically depleted P-bodies in MSCs, they failed to reprogram macrophages to suppress T cells (Fig. 1). Overall, our data demonstrate that hCT-MSCs reprogram macrophages to suppress a T cell response through P-bodies. This not only explains a potential in vivo mechanism how MSCs can confer long-term benefit after they are cleared but is a potential novel and manipulatable target to promote increased efficacy of MSCs in multiple inflammatory conditions.