Towards a Functional Cure for Diabetes Using Stem Cell-Derived Beta Cells: Are We There Yet?

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.

Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction

“…Stem cells are an invaluable tool for investigating the molecular mechanisms of monogenic diabetes and hold the promise of a potential curative treatment [ 141 ]. Studies using human islets from monogenic diabetes patients are not a real possibility since these cases only represent a small fraction of all diabetes cases.…”

Recent advances in tissue stem cells

“…One promising strategy is to derive transplantable β cells from embryonic stem cells (ESCs). Since insulin-producing cells were observed in a mixed cell population spontaneously differentiated human ESCs in 2001 (Assady et al, 2001), many exciting new advances have been achieved (reviewed by Bourgeois et al, 2021;Migliorini et al, 2021;Zhou et al, 2020b). Another route to generate transplantable β cells is through the generation of islet organoids directly derived from pancreatic tissues.…”

Advances in Pancreatic Islet Transplantation Sites for the Treatment of Diabetes

“…Strategies for mitigation, control, and treatment of diabetes have been the subject of intense research. Daily insulin injection therapy remains to be the standard care for patients with T1D, late-stage of T2D, and in some rare forms of diabetes ( 31 ). However, a daily insulin injection therapy, while life-saving, does not exactly recapitulate the effectiveness of endogenous control of blood glucose by β cells.…”

“…Recent advancements in the field of stem cells have brought us closer to addressing the shortage of cadaveric islets for use in transplantation. Various protocols utilizing human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) have been developed to differentiate these cells into β-like cells with key markers for mature pancreatic islets ( 39 – 45 ) ( 31 ). These stem cell-derived β-like cells are capable of sensing blood glucose levels and are also capable of secreting various levels of insulin when transplanted into animal models of diabetes.…”