mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation

Oren Levy1,2,3, Weian Zhao1,2,3,  Luke J. Mortensen4, Sarah LeBlanc1,2,3, Kyle Tsang1,2,3, Moyu Fu1,2,3, Joseph A. Phillips1,2,3, Vinay Sagar1,2,3, Priya Anandakumaran1,2,3, Jessica Ngai1,2,3, Cheryl H. Cui1,2,3, Peter Eimon5, Matthew Angel5, Charles P. Lin5, Mehmet Fatih Yanik5,6, Jeffrey M. Karp1,2,3 1Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, 2Harvard Stem Cell Institute, Cambridge, MA, 3Harvard—Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, MA, 4Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 5Department of Biological Engineering, 6Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA
Blood 122 (14): e23–e32, 2013  

Mesenchymal stem cells (MSCs) are promising candidates for cell-based therapy to treat several diseases and are compelling to consider as vehicles for delivery of biological agents. However, MSCs appear to act through a seemingly limited “hit-and-run” mode to quickly exert their therapeutic impact, mediated by several mechanisms, including a potent immunomodulatory secretome. Furthermore, MSC immunomodulatory properties are highly variable and the secretome composition following infusion is uncertain. To determine whether a transiently controlled antiinflammatory MSC secretome could be achieved at target sites of inflammation, we harnessed mRNA transfection to generate MSCs that simultaneously express functional rolling machinery (P-selectin glycoprotein ligand-1 [PSGL-1] and Sialyl-Lewisx [SLeX]) to rapidly target inflamed tissues and that express the potent immunosuppressive cytokine interleukin-10 (IL-10), which is not inherently produced by MSCs. Indeed, triple-transfected PSGL-1/SLeX/IL-10 MSCs transiently increased levels of IL-10 in the inflamed ear and showed a superior antiinflammatory effect in vivo, significantly reducing local inflammation following systemic administration. This was dependent on rapid localization of MSCs to the inflamed site. Overall, this study demonstrates that despite the rapid clearance of MSCs in vivo, engineered MSCs can be harnessed via a “hit-and-run” action for the targeted delivery of potent immunomodulatory factors to treat distant sites of inflammation.