Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 16, Pages 5896-5901Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1402087111
Keywords
GPCR; cellular therapeutics; synthetic biology
Categories
Funding
- National Institutes of Health (NIH) [R01 HL60664-07]
- NIH Nanomedicine Development Center [PN2EY016546]
- NIH [P50 GM08187]
- National Science Foundation Synthetic Biology Engineering Research Center, NIH [R01 GM084040]
- California Institute for Regenerative Medicine fellowship [TG2-01153]
- Howard Hughes Medical Institute
- Gladstone Institutes
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Directed migration of diverse cell types plays a critical role in biological processes ranging from development and morphogenesis to immune response, wound healing, and regeneration. However, techniques to direct, manipulate, and study cell migration in vitro and in vivo in a specific and facile manner are currently limited. We conceived of a strategy to achieve direct control over cell migration to arbitrary user-defined locations, independent of native chemotaxis receptors. Here, we show that genetic modification of cells with an engineered G protein-coupled receptor allows us to redirect their migration to a bioinert drug-like small molecule, clozapine-N-oxide (CNO). The engineered receptor and small-molecule ligand form an orthogonal pair: The receptor does not respond to native ligands, and the inert drug does not bind to native cells. CNO-responsive migration can be engineered into a variety of cell types, including neutrophils, T lymphocytes, keratinocytes, and endothelial cells. The engineered cells migrate up a gradient of the drug CNO and transmigrate through endothelial monolayers. Finally, we demonstrate that T lymphocytes modified with the engineered receptor can specifically migrate in vivo to CNO-releasing beads implanted in a live mouse. This technology provides a generalizable genetic tool to systematically perturb and control cell migration both in vitro and in vivo. In the future, this type of migration control could be a valuable module for engineering therapeutic cellular devices.
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