Discovery of novel anti-inflammatory proteins inspired by bone marrow mesenchymal stem cell secretions

Abstract

Bone marrow mesenchymal stem cells (MSCs) may soon become the first FDA-approved stem cell therapy for autoimmune and inflammatory disease. Our lab originally hypothesized that much of the therapeutic activity of MSCs may be attributed to molecules secreted by these cells. This thesis will test this hypothesis, with an emphasis on translational steps towards clinical product development, including the identification of novel proteins secreted by MSCs. The first part of the thesis consists of studies we performed to test whether MSC conditioned medium (MSC-CM) can treat rats undergoing cisplatin-induced acute kidney injury (AKI). When AKI rats were treated with MSC-CM, we observed a survival benefit and significant protection of renal function compared to controls. The second part of the thesis will describe the development of a device designed for sustained delivery of MSC secreted factors to dialysis-dependent AKI subjects. We tested these devices for cell function, stability and viability when subjected to conditions that model future clinical operation. Finally, inspired by the therapeutic capacity of MSC secreted factors, this thesis will conclude with the introduction of a new method that we developed to uncover novel anti-inflammatory proteins from MSCs. This method revealed four previously unidentified cytokine modulators, two of which we found significantly promote IL-1 0 and suppress TNF-a in mice challenged with endotoxin. When leveraged as novel therapeutics for lethal endotoxemic shock, these two most potent modulators protected mice and provided for a significant survival benefit compared to vehicle controls. Together, these results demonstrate the power of MSC secreted factors in the context of inflammatory disease, and propose new tactics for elucidating potent secreted products from cells.