Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Oren Levy1,
  2. Weian Zhao2,
  3. Luke J. Mortensen3,
  4. Sarah LeBlanc4,
  5. Kyle Tsang1,
  6. Moyu Fu1,
  7. Joseph A. Phillips5,
  8. Vinay Sagar1,
  9. Priya Anandakumaran1,
  10. Jessica Ngai1,
  11. Cheryl H. Cui1,
  12. Peter Eimon6,
  13. Matthew Angel6,
  14. Charles P. Lin3,
  15. Mehmet Fatih Yanik6, and
  16. Jeffrey M. Karp1,*
  1. 1 Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, United States;
  2. 2 Harvard Stem Cell Institute, Cambridge, MA, United States;
  3. 3 Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States;
  4. 4 Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, United States;
  5. 5 Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, United States;
  6. 6 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
  1. * Corresponding author; email: jeffkarp.bwh{at}gmail.com

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.