Stem Cell–Derived Islets: Next Steps for Histologic and Functional Assessment During Development as a Cellular Therapy for the Treatment of Diabetes

Type 1 diabetes (T1D) results from autoimmune destruction of the insulin-producing β-cells in the endocrine pancreatic islets of Langerhans. Patients are thus dependent on exogenous insulin therapy delivered by multiple daily injections or continuous subcutaneous infusion pumps to control elevated glucose levels and prevent the development of life-threatening ketoacidosis. Due to the pharmacokinetic and pharmacodynamic limitations and complexity of subcutaneous insulin delivery, most patients living today with T1D cannot achieve levels of glucose control recommended for the prevention of diabetes complications (1). Therefore, biologic insulin therapy delivered by β-cell replacement has long been hoped to supplant exogenous insulin therapy for T1D but has been realized only in the limited context of pancreas or isolated islet transplantation using deceased donor organs (2). Recent progress in the generation of functional islet β-cells from human stem cell sources (3) has reinvigorated hope for a one day limitless supply of islets for transplantation therapy (4).

Human embryonic stem cells (hESCs) differentiated to a pancreatic endoderm progenitor stage in vitro have the potential to further differentiate into functional pancreatic islets in vivo (5,6). Further differentiation to a pancreatic islet stage in vitro can generate cell clusters with the capacity for glucose-dependent insulin secretion before transplantation (7,8). While both approaches are capable of reversing streptozotocin-induced diabetes in immunodeficient mouse models, the use of pancreatic endoderm cells (PECs) has previously been accompanied by the sporadic growth of mesodermal cells reminiscent of the formation of teratomas. The use of pancreatic islet stage cells is hoped to minimize off-target differentiation; however, these later stage endocrine cells still undergo further in vivo differentiation and so may not fully eliminate the potential risks associated with …