Review The Human Endocrine Pancreas: New Insights on Replacement and Regeneration Juan Domínguez-Bendala, 1,2,3, * Giacomo Lanzoni, 1 Dagmar Klein, 1 Silvia Álvarez-Cubela, 1 and Ricardo L. Pastori 1,4,5, * Islet transplantation is an effective cell therapy for type 1 diabetes (T1D) but its clinical application is limited due to shortage of donors. After a decade-long period of exploration of potential alternative cell sources, the field has only recently zeroed in on two of them as the most likely to replace islets. These are pluripotent stem cells (PSCs) (through directed differentiation) and pancreatic non-endocrine cells (through directed differentiation or reprogramming). Here we review progress in both areas, including the initiation of Phase I/II clinical trials using human embryonic stem cell (hESc)-derived progenitors, advances in hESc differentiation in vitro, novel insights on the developmental plasticity of the pancreas, and groundbreaking new approaches to induce b cell conversion from the non-endocrine compartment without genetic manipulation. Diabetes Therapies Require Alternative Sources of Islets The insulin-producing b cells of the pancreas (see Glossary), alongside other endocrine cell types within the islets of Langerhans, are responsible for the maintenance of glucose homeostasis. In the autoimmune disorder known as T1D, b cells are targeted and destroyed by autoreactive T cells. Chronic insulin administration is a life-saving intervention but one that fails to prevent long-term complications that include blindness, vascular disease, and kidney failure. Islet transplantation from cadaveric donors is a successful cell therapy for T1D, especially since the development of steroid-free immunosuppression protocols [1] and, more recently, T cell-depleting interventions that ensure insulin independence rates up to 5 years post-transplantation with minimal compli- cations [2]. However, its general clinical application is limited by the need for lifelong immune suppression and the shortage of donors [1,3,4]. The latter – and arguably most pressing – problem could be addressed by using self-renewable cells with the potential to become b cells. The development of any such therapy may also have applications beyond T1D for type 2 diabetes (T2D), the most prevalent form of the disease. Notwithstanding its different etiology, many forms and/or stages of T2D are also characterized by insufficient insulin production and/or b cell loss and thus could benefit from the transplantation/regeneration of b cells. Several cell sources (e.g., mesenchymal, hematopoietic, fetal) scrutinized throughout the past decade and a half are no longer a primary focus for the development of b cell replacement strategies. Some of the key approaches presently explored include the use of PSCs (through directed differentiation), pancreatic non-endocrine cells (through directed differentiation or reprogramming), and expansion of pancreatic islet cells. Trends Stem cell therapies are finally coming of age in the context of pancreatic endo- crine regeneration for diabetes. Clinical trials aimed at testing the safety and efficacy of human embryonic stem cell- derived islet surrogates are already ongoing. If successful, these approaches are expected to lead to the phasing out of the use of cadaveric islets for trans- plantation, exponentially extending our ability to treat millions of type 1 dia- betes – and potentially also type 2 dia- betes – patients. Different cell populations within the pancreas can regenerate the endo- crine compartment through repro- gramming, replication, or stimulation of resident progenitors. The field has recently advanced to the point where these phenomena can be induced without the need for genetic manipulation, getting us closer to the design of viable clinical trials for b cell replenishment or endogenous regeneration. 1 Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA 2 Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA 3 Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, FL, USA TEM 1100 No. of Pages 10 Trends in Endocrinology & Metabolism, Month Year, Vol. xx, No. yy http://dx.doi.org/10.1016/j.tem.2015.12.003 1 © 2015 Elsevier Ltd. All rights reserved.