A small-molecule screen for enhanced homing of systemically infused cells.
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.
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139.|Harvard Stem Cell Institute, Cambridge, MA 02139.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139.
Oren
O
Levy
Harvard Stem Cell Institute, Cambridge, MA 02139.|Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
Luke J
LJ
Mortensen
Sanofi R&D , Centre de recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine Cédex, France.
Gerald
G
Boquet
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139.|Harvard Stem Cell Institute, Cambridge, MA 02139.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139.
Zhixiang
Z
Tong
Sanofi R&D , Centre de recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine Cédex, France.
Christelle
C
Perrault
Sanofi R&D , Centre de recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine Cédex, France.
Brigitte
B
Benhamou
Sanofi R&D , Centre de recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine Cédex, France.
Jidong
J
Zhang
Harvard Stem Cell Institute, Cambridge, MA 02139.|Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
Tara
T
Stratton
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139.|Harvard Stem Cell Institute, Cambridge, MA 02139.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139.
Edward
E
Han
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139.|Harvard Stem Cell Institute, Cambridge, MA 02139.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139.
Helia
H
Safaee
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139.|Harvard Stem Cell Institute, Cambridge, MA 02139.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139.
Juliet
J
Musabeyezu
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139.|Harvard Stem Cell Institute, Cambridge, MA 02139.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139.
Zijiang
Z
Yang
Sanofi R&D , Centre de recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine Cédex, France.
Marie-Christine
MC
Multon
Sanofi R&D, 270 Albany Street, Cambridge, Massachusetts 02139, USA.
Jonathan
J
Rothblatt
Sanofi R&D , Centre de recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine Cédex, France.
Jean-Francois
JF
Deleuze
Harvard Stem Cell Institute, Cambridge, MA 02139.|Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
Charles P
CP
Lin
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139.|Harvard Stem Cell Institute, Cambridge, MA 02139.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139.
Jeffrey M
JM
Karp
D000818:Animals; D040881:CD11a Antigen / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology / Q000628:therapy; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008301:Maleimides / Q000737:chemistry / Q000494:pharmacology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D015854:Up-Regulation
D040881:CD11a Antigen; C573420:ICAM1 protein, human; D007211:Indoles; D008070:Lipopolysaccharides; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D018799:Intercellular Adhesion Molecule-1; C071924:Ro 31-8425