Stem cells in diabetes: what has been achieved.

Beta-cell replacement therapy via islet transplantation has received renewed interest due to the recent improved success. In order to make such a therapy available to more than a few of the thousands of patients with diabetes, new sources of insulin-producing cells must be readily available. The most promising sources are stem cells, with efforts of deriving new beta-cells from both embryonic and adult stem cells. Several groups have reported generating insulin-producing cells from mouse embryonic stem cells. The strategies in the first two acclaimed reports were very different. One strategy, used by Soria's group, is gene trapping in which an introduced antibiotic resistance under the control of the insulin promoter allowed the selection of insulin-expressing cells that had spontaneously differentiated within embryoid bodies. Another strategy, used by McKay's group, manipulated culture conditions in a multistep protocol used for generating neural cells but with changed final conditions. Since these reports, there have been modifications of the protocols in efforts to improve the yields and maturity of the resulting cells. While it is unclear if the insulin-producing cells in any of these studies are truly mature beta-cells, these studies show the clear potential of embryonic stem cells and support optimism that similar results will be possible with human embryonic stem cells. We know that new beta-cells are generated throughout adult life, but the identity of adult pancreatic stem cells has been elusive. The potential for expansion and differentiation of pluripotent adult stem cells, whether from bone marrow or as non-pancreas tissue resident SP cells, is being explored but has not yet yielded insulin-producing tissue. In contrast, insulin-producing cells have been generated in vitro from adult pancreatic tissues. We have been examining the hypothesis that the functional source for new beta-cells in the adult pancreas are mature duct epithelial cells that have regressed or lost their mature phenotype after replication. Others have isolated putative stem cells from islets and ducts. For adult cells the issue of expansion as well as of differentiation is a question. The field of generating new beta-cells from stem cells, either embryonic or adult, is still in its infancy. Each new report has been met with a mixture of excitement and skepticism. With continued efforts and rigorous assessments, hopefully the potential of generating enough new beta-cells from stem cells will be realized.