Abstract
Poor homing of systemically infused cells to disease sites may limit the success of exogenous cell-based therapy. In this study, we screened 9,000 signal-transduction modulators to identify hits that increase mesenchymal stromal cell (MSC) surface expression of homing ligands that bind to intercellular adhesion molecule 1 (ICAM-1), such as CD11a. Pretreatment of MSCs with Ro-31-8425, an identified hit from this screen, increased MSC firm adhesion to an ICAM-1-coated substrate in vitro and enabled targeted delivery of systemically administered MSCs to inflamed sites in vivo in a CD11a- (and other ICAM-1-binding domains)-dependent manner. This resulted in a heightened anti-inflammatory response. This represents a new strategy for engineering cell homing to enhance therapeutic efficacy and validates CD11a and ICAM-1 as potential targets. Altogether, this multi-step screening process may significantly improve clinical outcomes of cell-based therapies.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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CD11a Antigen / genetics
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CD11a Antigen / metabolism
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Cell Adhesion / drug effects
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Cell Line
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Cell Movement
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High-Throughput Screening Assays
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Humans
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Indoles / chemistry
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Indoles / pharmacology
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Inflammation / chemically induced
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Inflammation / pathology
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Inflammation / therapy
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Intercellular Adhesion Molecule-1 / chemistry
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Intercellular Adhesion Molecule-1 / metabolism
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Lipopolysaccharides / toxicity
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Maleimides / chemistry
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Maleimides / pharmacology
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Mesenchymal Stem Cell Transplantation
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Mesenchymal Stem Cells / cytology*
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Mesenchymal Stem Cells / drug effects
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Mesenchymal Stem Cells / metabolism
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Mice
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Mice, Inbred C57BL
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Microscopy, Confocal
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Small Molecule Libraries / chemistry*
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Small Molecule Libraries / pharmacology
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Up-Regulation
Substances
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CD11a Antigen
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ICAM1 protein, human
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Indoles
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Lipopolysaccharides
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Maleimides
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Protein Kinase Inhibitors
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Small Molecule Libraries
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Intercellular Adhesion Molecule-1
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Ro 31-8425