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

Oren Levy, Weian Zhao, Luke J. Mortensen, Sarah LeBlanc, Kyle Tsang, Moyu Fu, Joseph A. Phillips, Vinay Sagar, Priya Anandakumaran, Jessica Ngai, Cheryl H. Cui, Peter Eimon, Matthew Angel, Charles P. Lin, Mehmet Fatih Yanik and Jeffrey M. Karp

Key points

  • mRNA transfection is an effective tool to simultaneously engineer MSCs for enhanced homing and improved secretome.

  • MSCs can be systemically targeted to sites of inflammation to achieve therapeutically relevant concentrations of biological agents.

Abstract

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 if a transiently controlled anti-inflammatory 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), that 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 anti-inflammatory 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.

  • Submitted April 4, 2013.
  • Accepted August 21, 2013.