Emerging diabetes therapies: Bringing back the ß-cells.

BACKGROUND: Stem cell therapies are finally coming of age as a viable alternative to pancreatic islet transplantation for the treatment of insulin-dependent diabetes. Several clinical trials using human embryonic stem cell (hESC)-derived ß-like cells are currently underway, with encouraging preliminary results. Remaining challenges notwithstanding, these strategies are widely expected to reduce our reliance on human isolated islets for transplantation procedures, making cell therapies available to millions of diabetic patients. At the same time, advances in our understanding of pancreatic cell plasticity and the molecular mechanisms behind ß-cell replication and regeneration have spawned a multitude of translational efforts aimed at inducing ß-cell replenishment in situ through pharmacological means, thus circumventing the need for transplantation. SCOPE OF REVIEW: We discuss here the current state of the art in hESC transplantation, as well as the parallel quest to discover agents capable of either preserving the residual mass of ß-cells or inducing their proliferation, transdifferentiation or differentiation from progenitor cells. MAJOR CONCLUSIONS: Stem cell-based replacement therapies in the mold of islet transplantation are already around the corner, but a permanent cure for type 1 diabetes will likely require the endogenous regeneration of ß-cells aided by interventions to restore the immune balance. The promise of current research avenues and a strong pipeline of clinical trials designed to tackle these challenges bode well for the realization of this goal.

Cellular Therapies and Regenerative Strategies for Diabetes - Proceeding of the STEMSO Conference.

Diabetes is now considered a growing global epidemic with sizable negative effects on patients' quality of life and life expectancy, and escalating economic impact (41% growth in the past five year), now representing health care ex-penditure impact of 256 Billion/year in the US alone. Objectives of cellular therapies and regenerative medicine strategies for treatment of diabetes are to reverse the disease condition and prevent the development of the severe chronic complications that can affect most organ systems in a large proportion of patients over time. Cell based therapies include the combination of immunomodulatory approaches aimed at restoring self tolerance (i.e., in the case of autoimmune diabetes) and at inducing permanent acceptance of transplanted tissues (in the case of allogeneic donors), or immune protection (i.e., engineered microenvironment and/or encapsulation) so that the immune system can no longer destroy the new insulin producing cells introduced either by regenerating, reprogramming or replacement. Several approaches are currently under evaluation for restoration of beta cell mass. The prototype strategy for Replacement is pancreatic islet transplantation, which is now an approved procedure in several countries. Reprogramming from non insulin-producing cells or Regeneration strategies could represent an appealing alternative to overcome shortage of deceased donor organs for transplantation. The selection of the most appropriate source for insulin producing cells is still not defined and the selected alternatives between replacement, reprogramming and regeneration strategies will be further developed in pre-clinical model systems and pilot clinical trials, while carefully assessing safety, efficacy and cost-effectiveness, as well as the challenges imposed by scaling up the selected technologies to meet the demand of the millions of affected patients who could benefit from these strategies.

Insulin protein and proliferation in ductal cells in the transplanted pancreas of patients with type 1 diabetes and recurrence of autoimmunity.

AIM/HYPOTHESIS: We investigated whether beta cell neoformation occurs in the transplanted pancreas in patients with type 1 diabetes who had received a simultaneous pancreas-kidney transplant (SPK) and later developed recurrence of autoimmunity. METHODS: We examined pancreas transplant biopsies from nine SPK patients with or without recurrent autoimmunity or recurrent diabetes and from 16 non-diabetic organ donors. Tissues were analysed by immunohistochemistry and immunofluorescence. RESULTS: Numerous cytokeratin-19 (CK-19)(+) pancreatic ductal cells stained for insulin in six SPK recipients with recurrent autoimmunity, in five of whom diabetes requiring insulin therapy recurred. These cells also stained for the transcription factor pancreatic-duodenal homeobox-1 (Pdx-1), which is implicated in pancreatic development and beta cell differentiation. The number of insulin(+) ductal cells varied, being highest in the patient with the most severe beta cell loss and lowest in the normoglycaemic patient. In the patient with the most severe beta cell loss, we detected insulin(+)CK-19(+)Pdx-1(+) cells staining for the proliferation-related Ki-67 antigen (Ki-67), indicating proliferation. We were unable to detect Ki-67(+) beta cells within the islets in any SPK patient. Some insulin(+)CK-19(-) ductal cells contained chromogranin A, suggesting further endocrine differentiation. Insulin(+) cells were rarely noted in the pancreas transplant ducts in three SPK patients without islet autoimmunity and in six of 16 non-diabetic organ donors; these insulin(+) cells were never CK-19(+). CONCLUSIONS/INTERPRETATION: Insulin(+) pancreatic ductal cells, some apparently proliferating, were found in the transplanted pancreas with recurrent islet autoimmunity/diabetes. Replicating beta cells were not detected within islets. The observed changes may represent attempts at tissue remodelling and beta cell regeneration involving ductal cells in the human transplanted pancreas, possibly stimulated by hyperglycaemia and chronic inflammation.