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Switching-On Survival and Repair Response Programs in Islet Transplants by Bone Marrow–Derived Vasculogenic Cells

¹ Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California
² Department of Pediatrics, Biomedical Genomics Microarray Facility, University of California, San Diego, La Jolla, California
³ Department of Medicine, Biomedical Genomics Microarray Facility, University of California, San Diego, La Jolla, California
⁴ The Sloan Kettering Cancer Center, New York, New York

Corresponding author: Laura Crisa, crisa{at}scripps.edu

OBJECTIVE—Vascular progenitors of bone marrow origin participate to neovascularization at sites of wound healing and transplantation. We hypothesized that the biological purpose of this bone marrow–derived vascular component is to contribute angiogenic and survival functions distinct from those provided by the local tissue-derived vasculature.

RESEARCH DESIGN AND METHODS AND RESULTS—To address this hypothesis, we investigated the functional impact of bone marrow–derived vascular cells on pancreatic islets engraftment using bone marrow–reconstituted Id1^+/–Id3^–/– mice, a model of bone marrow–derived vasculogenesis. We show that, in this model, bone marrow–derived vasculogenic cells primarily contribute to the formation of new blood vessels within islet transplants. In contrast, graft revascularization in a wild-type background occurs by tissue-derived blood vessels only. Using these distinct transplant models in which bone marrow–and tissue-derived vasculature are virtually mutually exclusive, we demonstrate that bone marrow–derived vasculogenic cells exhibit enhanced angiogenic functions and support prompt activation of islets survival pathways, which significantly impact on islets engraftment and function. Moreover, gene profiling of vascular and inflammatory cells of the grafts demonstrate that neovascularization by bone marrow–derived cells is accompanied by the activation of a genetic program uniquely tuned to downregulate harmful inflammatory responses and to promote tissue repair.

CONCLUSIONS—These studies uncover the biological significance of bone marrow–derived vasculogenic cells in the response to injury during transplantation. Enhancing the contribution of bone marrow–derived vasculogenic cells to transplantation sites may help to overcome both limited angiogenic responses of the adult tissue-derived vasculature and untoward effects of inflammation on transplant engraftment.

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