Abstract
Pre-treatment or priming of mesenchymal stem cells (MSC) prior to transplantation can significantly augment the immunosuppressive effect of MSC-based therapies. In this study, we screened a library of 1402 FDA-approved bioactive compounds to prime MSC. We identified tetrandrine as a potential hit that activates the secretion of prostaglandin E2 (PGE2), a potent immunosuppressive agent, by MSC. Tetrandrine increased MSC PGE2 secretion through the NF-κB/COX-2 signaling pathway. When co-cultured with mouse macrophages (RAW264.7), tetrandrine-primed MSC attenuated the level of TNF-α secreted by RAW264.7. Furthermore, systemic transplantation of primed MSC into a mouse ear skin inflammation model significantly reduced the level of TNF-α in the inflamed ear, compared to unprimed cells. Screening of small molecules to pre-condition cells prior to transplantation represents a promising strategy to boost the therapeutic potential of cell therapy.
Highlights
Engineering, and Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine, CA, US
We established a high-throughput screening (HTS) protocol to identify bioactive molecules that can enhance secretion of a candidate immunomodulatory molecule, Prostaglandin E2 (PGE2) that has been implicated as a key component of the Mesenchymal stem cells (MSC) secretome[8,23,24,25,26]
We found that incubating 1500 cells/well in 384-well format overnight and assaying 24 h later was best for cell metabolic activity and for measuring secreted PGE2 by Homogeneous Time-Resolved Fluorescence (HTRF) technology
Summary
Engineering, and Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine, CA, US. Et al reported that MSC spheroids formed in hanging drops express high amount of TNF-αstimulated gene/protein 6 (TSG-6), stanniocalcin-1, IL-24, TNF-α-related apoptosis inducing ligand, and CD8221. MSC engineered with budesonide-loaded PLGA microparticles have been explored to enhance IDO activity[22]. Small molecule pre-conditioning represents an attractive approach that is amenable to treatment of large numbers of cells for clinical scale production, yet to date, most studies modified MSC function by utilizing limited selection of well-established factors to manipulate classic immunoregulatory genes. We established a high-throughput screening (HTS) protocol to identify bioactive molecules that can enhance secretion of a candidate immunomodulatory molecule, Prostaglandin E2 (PGE2) that has been implicated as a key component of the MSC secretome[8,23,24,25,26]
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