title: mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation.
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 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-Lewis(x) [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.
authors: Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA;
authors: Oren
authors: O
authors: Levy
authors: Weian
authors: W
authors: Zhao
authors: Luke J
authors: LJ
authors: Mortensen
authors: Sarah
authors: S
authors: Leblanc
authors: Kyle
authors: K
authors: Tsang
authors: Moyu
authors: M
authors: Fu
authors: Joseph A
authors: JA
authors: Phillips
authors: Vinay
authors: V
authors: Sagar
authors: Priya
authors: P
authors: Anandakumaran
authors: Jessica
authors: J
authors: Ngai
authors: Cheryl H
authors: CH
authors: Cui
authors: Peter
authors: P
authors: Eimon
authors: Matthew
authors: M
authors: Angel
authors: Charles P
authors: CP
authors: Lin
authors: Mehmet Fatih
authors: MF
authors: Yanik
authors: Jeffrey M
authors: JM
authors: Karp
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods; D005818:Genetic Engineering / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007249:Inflammation / Q000188:drug therapy; D016753:Interleukin-10 / Q000008:administration & dosage*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger; D014162:Transfection
chemical_list: D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016753:Interleukin-10
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