A perfect islet: reviewing recent protocol developments and proposing strategies for stem cell derived functional pancreatic islets

Abstract

The search for an effective cell replacement therapy for diabetes has driven the development of “perfect” pancreatic islets from human pluripotent stem cells (hPSCs). These hPSC-derived pancreatic islet-like β cells can overcome the limitations for disease modelling, drug development and transplantation therapies in diabetes. Nevertheless, challenges remain in generating fully functional and mature β cells from hPSCs. This review underscores the significant efforts made by researchers to optimize various differentiation protocols aimed at enhancing the efficiency and quality of hPSC-derived pancreatic islets and proposes methods for their improvement. By emulating the natural developmental processes of pancreatic embryogenesis, specific growth factors, signaling molecules and culture conditions are employed to guide hPSCs towards the formation of mature β cells capable of secreting insulin in response to glucose. However, the efficiency of these protocols varies greatly among different human embryonic stem cell (hESC) and induced pluripotent stem cell (hiPSC) lines. This variability poses a particular challenge for generating patient-specific β cells. Despite recent advancements, the ultimate goal remains to develop a highly efficient directed differentiation protocol that is applicable across all genetic backgrounds of hPSCs. Although progress has been made, further research is required to optimize the protocols and characterization methods that could ensure the safety and efficacy of hPSC-derived pancreatic islets before they can be utilized in clinical settings.

1. Introduction

Diabetes mellitus (DM) is a highly common chronic metabolic disorder, primarily characterized by hyperglycemia, affecting millions of the population worldwide with an exponential projected growth from 463 million in 2019 to 700 million in 2045 [1]. Type 1 DM (T1D) and Type 2 DM (T2D) are the most prevalent forms of diabetes observed in clinical practice [1]. In T1D, pancreatic islet β cells undergo autoimmune destruction leading to a lack of insulin production. For that reason, optimal treatment of TID is vital, and lack of proper management can result in severe complications. In the case of T2D, there is insufficient insulin production due to β cell loss through apoptosis, together with impaired insulin sensitivity in peripheral tissues resulting in chronic secondary complications [2].

The current treatment strategies for DM include the continuous routine administration of exogenous insulin which is the only economical mode of treatment available for T1D, and also a common mainstay treatment for T2D alongside pharmaceutical agents and bariatric surgery [2]. Pancreatic islet transplantation, a standout treatment option particularly used in the management of T1D, has been shown to have clinical benefits, providing sustained glucose-sensitive insulin production together with a significantly reduced need for exogenous insulin [3]. However, given the scarcity of obtaining cadaveric donor islets and the life-long dependence on immunosuppressive medications, islet transplantation is viewed as an impractical option for clinical implementation. Therefore, an unmet need exists for effective alternative therapies that offer long-term relapse-free disease remission with minimum adverse effects [4].

Emerging reports highlight the use of stem cell-derived pancreatic β cells (SC-β cells) and islets (SC-islets) as a promising alternative to overcome the shortage of donor islets [5, 6]. Over the past few decades, many investigators have focused on generating protocols that delineate the differentiation of functional pancreatic islets from human pluripotent stem cells.