Abstract
Diabetes mellitus is a pandemic metabolic disorder that results from either the autoimmune destruction or the dysfunction of insulin-producing pancreatic beta cells. A promising cure is beta cell replacement through the transplantation of islets of Langerhans. However, donor shortage hinders the widespread implementation of this therapy. Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, represent an attractive alternative beta cell source for transplantation. Although major advances over the past two decades have led to the generation of stem cell-derived beta-like cells that share many features with genuine beta cells, producing fully mature beta cells remains challenging. Here, we review the current status of beta cell differentiation protocols and highlight specific challenges that are associated with producing mature beta cells. We address the challenges and opportunities that are offered by monogenic forms of diabetes. Finally, we discuss the remaining hurdles for clinical application of stem cell-derived beta cells and the status of ongoing clinical trials.
Highlights
Pancreatic beta cells are critical regulators of blood glucose homeostasis by their unique ability to produce and secrete insulin in response to changing blood glucose levels
T1D is marked by absolute insulin deficiency following autoimmune-mediated beta cell loss [2], while type 2 diabetes (T2D) is caused by relative insulin deficiency due to beta cell dysfunction, often in the context of peripheral insulin resistance [3]
Monogenic forms of diabetes result from single gene mutations and they are characterized by beta cell dysfunction, to varying degrees of severity [4]
Summary
Pancreatic beta cells are critical regulators of blood glucose homeostasis by their unique ability to produce and secrete insulin in response to changing blood glucose levels. Beta cell replacement proves to be superior to insulin administration with regard to overall metabolic control, prevention of severe hypoglycemia, and delaying the progression of micro- and macrovascular complications [6,7,8,9] Despite this proof-of-principle for beta cell replacement as a genuine cure, donor islet transplantation is unattainable for the vast majority of diabetic patients for several reasons. Glucose is phosphorylated by glucokinase (GCK) and is used to generate ATP through oxidative phosphorylation This rise in ATP increases the ATP/ADP ratio, which, in turn, leads to the closure of ATP-sensitive potassium (KATP) channels and cell membrane depolarization. Mathematical modeling of the accumulation of lipofuscin bodies in human beta cells suggests that, after the age of 20 years, long-lived beta cells age with the body [35,36]
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