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

doi:10.1016/j.celrep.2015.01.057

Cell Reports (Mar 2015)

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

DOI: https://doi.org/10.1016/j.celrep.2015.01.057
Journal volume & issue: Vol. 10, no. 8
pp. 1261 – 1268

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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