436 Bone Marrow Cells Bone marrow cell transplantation is suggested as a therapy to improve islet function. In addition to possible immune protection, direct benefits to the islets have been shown. A study by Ianus et al. [38] observed that transplantation of male bone marrow cells expressing green fluorescent protein (GFP) into lethally irradiated female recipient mice resulted in positivity for Y chromosome and GFP in 1.7% to 3% of pancreatic islet cells. These cells also expressed certain β-cell genes and transcription factors, and the authors concluded that bone marrow stem cells can differentiate into β cells. Hess et al. [39] noted a similar frequency of insulin-positive GFP-positive cells but did not ascribe this to direct differentiation. Other reports could not confirm differentiation of bone marrow cells into β cells in pancreatic injury and transplant models [40]. In these studies, migration to the pancreas was observed in addition to the amelioration of hyperglycemia and a partial or significant increase in β-cell mass, but no transdiffer- entiation of cells into β cells was seen [40]. Collectively, these studies indicate that bone marrow cells do not differentiate into β cells, but indirectly support β-cell function by either adopting a hematopoietic or endothelial cell fate or evoking the proliferation of recipient endothe- lial cells [40]. Mesenchymal Stromal Cells One subset of progenitor cell that can be isolated from bone marrow are multipotent mesenchymal stromal cells (MSCs). These are a heterogenous population that can differentiate into cell types of the mesoderm embryonic lineage (osteoblasts, chondrocytes, and adipocytes), and experimentally have been shown to have wider differenti- ation capacity. In vitro they adhere and proliferate on tissue culture plastic in colonies and maintain a fibroblast-like morphology. The interaction between MSCs and islets was demonstrated by Sordi et al. [41], who showed in a bone marrow transplantation model that GFP-positive bone marrow cells migrated to islets and, once isolated, demon- strated an MSC phenotype and the ability to differentiate into osteoblasts. Following this, studies using induced diabetes mouse models confirmed that MSC-islet co- transplantation not only reversed diabetes but also signif- icantly increased the number of recipient islets [42, 43]. Similarly, co-infusion of MSCs with a small number of islets allowed the return of normoglycemia and, moreover, an increase in capillary density was noted in these grafts compared with islets alone [44]. Other in vitro studies show that islets co-cultured with MSCs have higher levels of anti- apoptotic signaling molecules [45] and hypoxia-resistant molecules under hypoxic conditions [46]. Curr Diab Rep (2011) 11:434–444 MSCs also have immunoregulatory activities. With respect to islet transplantation, it was shown that a murine stromal cell line was able to prevent graft rejection in a major histocompatibility complex–mismatched islet trans- plantation model [47]. Matrix metalloproteinases (MMPs), specifically MMP-2 and −9, were speculated to mediate the protective effects seen after in vivo administration of MSCs with allogenic islets [48]. Furthermore, it was found that MSCs were capable of reducing islet infiltration and maintaining interleukin-10–secreting regulatory (FOXP3+) T cells in an autoimmune diabetes model [49]. These results were extended to a non-human primate model in which allo-MSC infusion–increased peripheral T-regulatory cells coincided with stable islet allograft function [50]. In view of the numerous avenues to protect islet cell grafts and improve their function, it follows that strategies to implement and optimize the addition of growth factors, proteins, and accessory cells to islets should be considered. Also, carriers to co-localize islets and their support factors should be explored. Improving an Islet’s Home Comfort and Guidance The housing of islets within a biomaterial at alternate transplantation sites is a potential therapeutic option. Material for such a therapy can be biologically derived or synthetically made. In the past few years there has been a propensity to focus on the glycosaminoglycan, heparin, and synthetic biodegradable materials as carriers for islet endocrine cells. Heparin Heparin is a complex polymer that interacts with numerous enzymes and proteins in the body. Heparin is commonly used as an anticoagulant, but also contains binding sites for several growth factors and chemokines [51]. Heparin binding has previously been used to improve the biocom- patibility of biomaterials for transplantation. Under this concept, Johansson et al. [37] directly heparinized the surface of islets to render them blood biocompatible. By immobilizing heparin to islets, they reasoned that this could inhibit coagulation and complement activation thereby reducing IBMIRs and intraportal islet loss. Using a biotin and avidin coating approach, they were able to transplant heparinized islets into a diabetic mouse and pig model. Blood glucose of mice transplanted with heparinized islets was normalized 10 days post-transplantation and a decrease in intraluminal clotting was observed in pigs transplanted with heparinized islets compared with untreated islets [52].