Curr Diab Rep (2011) 11:434–444 the source of which is still unidentified [15, 16]. Cell to cell contacts between β cells, facilitated by several transmem- brane proteins, are important for optimal insulin expression, content, and glucose-stimulated insulin secretion (GSIS) [17, 18]. β and α cells appear to have reciprocal secretory responses that cooperate to maintain glycemic stability [19]. Because of the β to α cell blood flow, the relationship between insulin and glucagon secretion is hypothesized to be determined by β-cell paracrine effects on α cells. However, β cells express glucagon receptors and these are involved in the glucose competence of β-cell insulin secretion [20]. The tight relationships between the major endocrine islet cells are supported by the tri-laminar architecture of human islets whereby one layer of β cells appears to be sandwiched between two α cell–enriched layers [21]. Islets are also innervated with neurons from parasympathetic and sympathetic nervous systems. Inter- actions between parasympathetic neurons and β cells activate specific receptors to promote GSIS. The opposite occurs from sympathetic neuronal input to inhibit insulin secretion [22]. In addition to interactions within the islet, the β cell also receives important signals from non-pancreatic tissues. β Cells are reported to interact with the liver, bone, fat, and gut [12]. Perhaps the best known example is the communication that occurs between the endocrine cells of the intestine and the β cells. By binding to specific G-protein-coupled receptors on the β cell, incretins, which are secreted by the enteroendocrine cells, stimulate insulin secretion [23]. Islet transplantation requires isolation of the islets from the remainder of the pancreas. This process involves enzymatic digestion of the pancreas and purification of the islets via density centrifugation [1], and destroys the vasculature and nerve distribution within islets. Moreover, connections to the rest of the pancreas and potentially outside the pancreas are also lost [24]. To recreate this β-cell niche shortly after transplantation is likely to be beneficial for β-cell function and survival. Islets and Growth Factors/Proteins Vascular Endothelial Growth Factor (VEGF-A) Newly transplanted islets require the process of angiogen- esis to establish adequate blood supply for survival post transplantation. This process occurs over a 2- to 4-week period in small [25, 26] and large animal [27] models, and is aided by the endothelial cell mitogen, VEGF-A. β Cells secrete VEGF-A under normal conditions [13, 14, 28] and it has been shown in vitro that hypoxic conditions increase VEGF-A protein expression, which may act as the initiator 435 of re-vascularization after transplantation [28]. It appears that β-cell production of VEGF-A is required for the formation of new vessels and a competent islet vasculature, because in animal models it is shown that increased blood flow and normoglycemia is achieved by VEGF-A transgene expression in transplanted islets, but not with exogenous VEGF-A treatment [29]. The importance of β-cell VEGF-A secretion was confirmed in a knockout VEGF-A mouse model in which VEGF-A–deficient islets had markedly reduced vascular density 1 month after they were trans- planted into a nondiabetic (NOD)–severe combined immu- nodeficiency mouse [30]. Extracellular Matrix Proteins The basement membrane contains several extracellular matrix proteins such as laminins and collagens that provide support for β-cell function via β1 integrin receptors [13– 15]. The importance of extracellular membrane proteins was demonstrated by the observation that a laminin 5–rich matrix allows β-cell spreading via α6β1 integrins [31] with decreased apoptosis [32], enhanced expression of cell cycle proteins [33], and improved insulin secretion of rat β cells [31, 33]. Islets and Accessory Cells Endothelial Cells Although β-cell signals are important for the vascular network and proper islet function, the source of endo- thelial cells can vary. Experimentally, it is shown that endothelial cells can be derived from progenitors in the bone marrow. Several studies have shown that endothe- lial reporter gene–positive cells are located within islets after transplantation of bone marrow from mice with endothelial reporter transgenes [34, 35]. It is further shown that islet graft vasculogenesis from bone marrow precursors is superior to tissue-derived vasculogenesis and results in better islet function post transplant [36]. The benefits of endothelial cell or endothelial precursor cells to transplanted islets have been investigated in diverse settings. Johansson et al. [37] combined the revasculari- zation properties of endothelial cells and their ability to act as a barrier and created a human endothelial cell coating on human islets prior to transplantation in an effort to protect islets from instant blood-mediated inflammatory reactions (IBMIRs). When transplanted into mice, these composite grafts provoked less activation of coagulation and complement and less infiltrating immune cells than non-coated islets, providing proof of concept for such a strategy [37].