A Small-Molecule Screen for Enhanced Homing of Systemically Infused Cells
Author(s)Levy, Oren; Mortensen, Luke J.; Boquet, Gerald; Tong, Zhixiang; Perrault, Christelle; Benhamou, Brigitte; Zhang, Jidong; Stratton, Tara; Han, Edward; Safaee, Helia; Musabeyezu, Juliet; Yang, Zijiang; Multon, Marie-Christine; Rothblatt, Jonathan; Deleuze, Jean-Francois; Lin, Charles P.; Karp, Jeffrey Michael; ... Show more Show less
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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.
DepartmentHarvard University--MIT Division of Health Sciences and Technology
Levy, Oren, Luke J. Mortensen, Gerald Boquet, Zhixiang Tong, Christelle Perrault, Brigitte Benhamou, Jidong Zhang, et al. “A Small-Molecule Screen for Enhanced Homing of Systemically Infused Cells.” Cell Reports 10, no. 8 (March 2015): 1261–1268.
Final published version