Ephrin-B2-expressing natural killer cells induce angiogenesis

Background: Therapeutic angiogenesis aims to induce new blood vessel growth in ischemic tissues; however, previous clinical trials have had limited success. Studies of uterine angiogenesis revealed a specialized subset of natural killer (NK) cells, called uterine NK (uNK) cells, which have unique proangiogenic abilities. Methods: We show that uNK cells in mice express ephrin-B2, a regulator of angiogenesis, to induce tubule formation in an ex vivo coculture tubule formation assay. We next induced the expression of ephrin-B2 by splenic NK (sNK) cells harvested from male mice. Results: We showed that induced NK (iNK) cells can also instruct endothelial cells to form tubules using ephrin-B2. Conclusions: We concluded that Ephrin-B2 is a marker of proangiogenic uNK cells and that a proangiogenic phenotype characterized by ephrin-B2 can be induced in sNK cells to induce therapeutic angiogenesis. : Clinical significance: Peripheral arterial disease threatens puts another 2 million limbs at risk for amputation annually; however, the clinical trials aimed at inducing angiogenesis within ischemic limbs have yielded disappointing results. New molecular therapies should be developed to address this. Like chimeric antigen receptor T cell therapy for melanoma, engineering a patient’s own cells into a population of proangiogenic cells represents a novel strategy to induce angiogenesis. Previous studies have shown that induction of a proangiogenic phenotype in natural killer cells was able to improve perfusion in the placentas of mice. Dissecting the molecular mechanisms behind these phenomena will elucidate the specific molecular targets required, and streamline the cell engineering protocol. We show that induction on natural killer cells of ephrin-B2, a proangiogenic cell membrane receptor that controls angiogenesis throughout life, induces a proangiogenic phenotype in these cells, which is the first step to a cell-based therapy for critical ischemia.