Revascularization of islet transplants has been shown to be supported by blood vessels developing from the host's vasculature surrounding the site of implant. However, recent reports indicate that angiogenesis at sites of injury may also recruit bone marrow-derived endothelial progenitors to the newly forming vessels. We have previously shown that endothelial progenitors circulating in human cord blood can be recruited and mature into endothelial cells at sites of transplant engraftment. Most recently, using bone marrow reconstituted Id1/ld3 deficient mice, a model of bone marrow-derived vasculogenesis, we demonstrated that bone marrow-derived vessels exhibit a highly angiogeneic phenotype in vivo, significantly enhancing engraftment and function of islet transplants, as compared to tissue-derived blood vessels. Furthermore, we show that bone marrow-derived endothelial cells are developmentally and functionally distinct from those derived from pre-existing blood vessels, as they maintain phenotypic hallmarks of early and myeloid hemopoietic precursors and exhibit cytokine and chemokine profiles consistent with limited capabilities to recruit and activate immune cells. Thus, we hypothesize that a biological role of bone marrow-derived endothelial cells is to provide efficient angiogenic functions and """"""""compartimentalize"""""""" immune responses at site of healing or tissue engraftment. Our objective is to test this hypothesis by using the Id1ld3-/- mouse model of bone marrow-derived vasculogenesis. In this model, there is a tissue defective angiogenesis that can be rescued by reconstitution with wild type bone marrow, allowing new blood vessels to develop virtually entirely from endothelial progenitors of bone marrow origin. Hence, this model provides a powerful tool to discern the possibly unique functions of the endothelium of hemopoietic origin from those contributed by tissue-derived endothelium and test their relevance to transplant engraftment. Thus, our aims are: 1) To characterize the angiogenic properties of bone marrow-derived vs. tissue-derived endothelium in the engraftment and long-term function of """"""""syngeneic"""""""" islet transplants. 2) To define cellular and molecular pathways of leukocyte/endothelial interactions specific to bone marrow and tissue-derived endothelium. 3) To study the functions of bone marrow-derived vasculature in the engraftment of """"""""allogeneic"""""""" pancreatic islet transplants, in vivo. This line of studies may help designing novel strategies to control immune responses and improve engraftment at site of transplantation.
| Jimenez-Caliani, Antonio J; Pillich, Rudolf; Yang, Wendy et al. (2017) ?E-Catenin Is a Positive Regulator of Pancreatic Islet Cell Lineage Differentiation. Cell Rep 20:1295-1306 |
| Mussar, Kristin; Tucker, Andrew; McLennan, Linsey et al. (2014) Macrophage/epithelium cross-talk regulates cell cycle progression and migration in pancreatic progenitors. PLoS One 9:e89492 |
| Diaferia, Giuseppe R; Jimenez-Caliani, Antonio J; Ranjitkar, Prerana et al. (2013) ?1 integrin is a crucial regulator of pancreatic ?-cell expansion. Development 140:3360-72 |
| Yebra, Mayra; Diaferia, Giuseppe R; Montgomery, Anthony M P et al. (2011) Endothelium-derived Netrin-4 supports pancreatic epithelial cell adhesion and differentiation through integrins ?2?1 and ?3?1. PLoS One 6:e22750 |
| Miller, Robyn; Cirulli, Vincenzo; Diaferia, Giuseppe R et al. (2008) Switching-on survival and repair response programs in islet transplants by bone marrow-derived vasculogenic cells. Diabetes 57:2402-12 |
