Islets are composed mostly of -cells, and therefore stem cell research has concentrated on generating purified -cells, neglecting the other endocrine cell types in the islet. We investigated the presence of endocrine non--cells after islet transplantation. In addition, we studied whether the transplantation of pure -cells, in volumes similar to that used in islet transplantation, would suffice to reverse hyperglycemia in diabetic mice. Rat islets were dispersed and -cells were purified by fluorescence-activated cell sorting according to their endogenous fluorescence. After reaggregation, 600 islet equivalents of the purified -cell aggregates were implanted into diabetic SCID mice. In mice implanted with -cell-enriched aggregates, the hyperglycemia was reversed and good graft function over a 12-week period was observed with regard to glucose and insulin levels, glucose tolerance tests, and graft insulin content. The endocrine cell composition of the -cell-enriched aggregates remained constant; before and 12 weeks after transplantation, the -cell- I slets of Langerhans consist of four main endocrine cell types: insulin-producing -cells, glucagon-producing ␣-cells, somatostatin-producing ␦-cells, and pancreatic polypeptide-producing PP cells. The most abundant cell is the -cell, which makes up ϳ60 -80% of islet cells in most mammalian species (1). The replacement of the -cells by islet or pancreas transplantation is presently the only treatment of type 1 diabetes that can render the patient insulin independent (2,3). However, the supply of donor pancreases is severely limited, and the demand is far greater than the supply. To overcome this problem, much effort has been made in trying to derive -cells from embryonic stem cells (4 -7) and other putative adult stem cells, such as pancreatic duct cells (8), bone marrow cells (9), and acinar cells (10). This would potentially create an unlimited supply of -cells for transplantation purposes. Moreover, it can be envisaged that the -cells generated in vitro could be genetically manipulated to confer protection against damage after transplantation (11). It may be that stem cell technology will find a way to produce -cells but not islet non--cells. Therefore, it is important to know whether a pure -cell graft can effectively reverse hyperglycemia. The importance of the non--cells in the physiology of maintaining normoglycemia is well known (12). However, it is not clear that the non--cells of islets have a meaningful local influence on -cell function. In fact, the microvasculature of the islet and functional studies indicate that non--cells are downstream from -cell secretion, suggesting that most -cells see very little intraislet glucagon or somatostatin (13,14). Also, there are nonendocrine cell types present in the islets, including endothelial cells, which could potentially have an impact on islet transplantation outcome (15,16). To obtain a purified population of -cells, the islets had to be dispersed into single cells. Our initial study theref...
