TY - JOUR
T1 - MRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation
AU - Levy, Oren
AU - Zhao, Weian
AU - Mortensen, Luke J.
AU - LeBlanc, Sarah
AU - Tsang, Kyle
AU - Fu, Moyu
AU - Phillips, Joseph A.
AU - Sagar, Vinay
AU - Anandakumaran, Priya
AU - Ngai, Jessica
AU - Cui, Cheryl H.
AU - Eimon, Peter
AU - Angel, Matthew
AU - Lin, Charles P.
AU - Yanik, Mehmet Fatih
AU - Karp, Jeffrey M.
N1 - Publisher Copyright:
© 2013 by The American Society of Hematology.
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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-transfectedPSGL-1/SLeX/IL-10MSCs transiently increased levels of IL-10 in the inflamed ear andshowed 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.
AB - 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-transfectedPSGL-1/SLeX/IL-10MSCs transiently increased levels of IL-10 in the inflamed ear andshowed 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.
UR - http://www.scopus.com/inward/record.url?scp=84885111559&partnerID=8YFLogxK
U2 - 10.1182/blood-2013-04-495119
DO - 10.1182/blood-2013-04-495119
M3 - Article
C2 - 23980067
AN - SCOPUS:84885111559
SN - 0006-4971
VL - 122
SP - e23-e32
JO - Blood
JF - Blood
IS - 14
ER -