A Small-Molecule Screen for Enhanced Homing of Systemically Infused Cells
Oren Levy,
Luke J. Mortensen,
Gerald Boquet,
Zhixiang Tong,
Christelle Perrault,
Brigitte Benhamou,
Jidong Zhang,
Tara Stratton,
Edward Han,
Helia Safaee,
Juliet Musabeyezu,
Zijiang Yang,
Marie-Christine Multon,
Jonathan Rothblatt,
Jean-Francois Deleuze,
Charles P. Lin,
Jeffrey M. Karp
Affiliations
Oren Levy
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
Luke J. Mortensen
Harvard Stem Cell Institute, Cambridge, MA 02139, USA
Gerald Boquet
Sanofi R&D, Centre de Recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine, France
Zhixiang Tong
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
Christelle Perrault
Sanofi R&D, Centre de Recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine, France
Brigitte Benhamou
Sanofi R&D, Centre de Recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine, France
Jidong Zhang
Sanofi R&D, Centre de Recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine, France
Tara Stratton
Harvard Stem Cell Institute, Cambridge, MA 02139, USA
Edward Han
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
Helia Safaee
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
Juliet Musabeyezu
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
Zijiang Yang
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
Marie-Christine Multon
Sanofi R&D, Centre de Recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine, France
Jonathan Rothblatt
Sanofi R&D, 270 Albany Street, Cambridge, MA 02139, USA
Jean-Francois Deleuze
Sanofi R&D, Centre de Recherche Vitry-Alfortville, 13 quai Jules Guesde, 94403 Vitry-sur-Seine, France
Charles P. Lin
Harvard Stem Cell Institute, Cambridge, MA 02139, USA
Jeffrey M. Karp
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
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.
