Sources of beta-cells for human cell-based therapies for diabetes

Recent progress in islet transplantation coupled with the extremely limited supply of primary human islets has spurred the search for alternative sources of beta-cells for transplantation therapy in treating diabetes. Many potential sources of cells are being explored, including embryonic and adult stem cells, identification of intrapancreatic precursor cells, and human beta-cell lines. Here, we review the promise and problems with those cell sources, focusing on our studies in developing functional human beta-cell lines. Those efforts involve a two-step process in which the first is to introduce growth stimulatory genes that induce human beta-cells to enter the cell cycle. Immortalization can then be achieved by expressing the hTERT telomerase subunit. The second step is to induce differentiation. This involves a complex set of manipulations, including the expression of the important beta-cell transcription factor PDX-1. Although PDX-1 is critical for promoting beta-cell differentiation, we do not find increased expression of the glucagon-like peptide-1 receptor, a gene that has been reported to be induced by PDX-1. Further understanding of the factors governing beta-cell development are likely to be required before a robust cell-based therapy is available for the treatment of diabetes.