Tissue engineering of decellularized pancreas scaffolds for regenerative medicine in diabetes.

Diabetes mellitus is a global disease requiring long-term treatment and monitoring. At present, pancreas or islet transplantation is the only reliable treatment for achieving stable euglycemia in Type I diabetes patients. However, the shortage of viable pancreata for transplantation limits the use of this therapy for the majority of patients. Organ decellularization and recellularization is emerging as a promising solution to overcome the shortage of viable organs for transplantation by providing a potential alternative source of donor organs. Several studies on decellularization and recellularization of rodent, porcine, and human pancreata have been performed, and show promise for generating usable decellularized pancreas scaffolds for subsequent recellularization and transplantation. In this state-of-the-art review, we provide an overview of the latest advances in pancreas decellularization, recellularization, and revascularization. We also discuss clinical considerations such as potential transplantation sites, donor source, and immune considerations. We conclude with an outlook on the remaining work that needs to be done in order to realize the goal of using this technology to create bioengineered pancreata for transplantation in diabetes patients. STATEMENT OF SIGNIFICANCE: Pancreas or islet transplantation is a means of providing insulin-independence in diabetes patients. However, due to the shortage of viable pancreata, whole-organ decellularization and recellularization is emerging as a promising solution to overcome organ shortage for transplantation. Several studies on decellularization and recellularization of rodent, porcine, and human pancreata have shown promise for generating usable decellularized pancreas scaffolds for subsequent recellularization and transplantation. In this state-of-the-art review, we highlight the latest advances in pancreas decellularization, recellularization, and revascularization. We also discuss clinical considerations such as potential transplantation sites, donor source, and immune considerations. We conclude with future work that needs to be done in order to realize clinical translation of bioengineered pancreata for transplantation in diabetes patients.

Generating pancreatic beta-like cells from human pluripotent stem cells.

Diabetes is a major healthcare burden globally, affecting over 463 million people today, according to the International Diabetes Federation. The most common types of diabetes are Type I diabetes (T1D) and Type II diabetes (T2D), characterized by hyperglycemia due to autoimmune destruction of ß cells (T1D) and ß cell dysfunction, usually on a background of insulin resistance (T2D). There is currently no cure for diabetes, and patients with T1D require lifelong insulin therapy. Additionally, while most cases of T2D can be managed by lifestyle and diet modifications, with or without antidiabetic drugs, severe cases of T2D may also require insulin therapy. The only means to restore stable euglycemia in these patients is now via whole pancreas or islet transplantation. However, this is limited by the scarcity of donors. In recent years, advances in human pluripotent stem cell (hPSC) technologies and pancreatic ß cell differentiation protocols have opened up new potential avenues for cell replacement therapies for diabetes. These advances have also created opportunities to use hPSC-derived ß-like cells for studies of disease mechanisms and drug discovery, which in turn have the potential to lead to better therapies for diabetes patients. Here, we describe the protocol used in our laboratory to generate ß-like cells from hPSCs to study the mechanisms underlying various types of diabetes.

Manufacturing clinical-grade human induced pluripotent stem cell-derived beta cells for diabetes treatment.

The unlimited proliferative capacity of human pluripotent stem cells (hPSCs) fortifies it as one of the most attractive sources for cell therapy application in diabetes. In the past two decades, vast research efforts have been invested in developing strategies to differentiate hPSCs into clinically suitable insulin-producing endocrine cells or functional beta cells (ß cells). With the end goal being clinical translation, it is critical for hPSCs and insulin-producing ß cells to be derived, handled, stored, maintained and expanded with clinical compliance. This review focuses on the key processes and guidelines for clinical translation of human induced pluripotent stem cell (hiPSC)-derived ß cells for diabetes cell therapy. Here, we discuss the (1) key considerations of manufacturing clinical-grade hiPSCs, (2) scale-up and differentiation of clinical-grade hiPSCs into ß cells in clinically compliant conditions and (3) mandatory quality control and product release criteria necessitated by various regulatory bodies to approve the use of the cell-based products.

Metformin Perturbs Pancreatic Differentiation From Human Embryonic Stem Cells.

Metformin is becoming a popular treatment before and during pregnancy, but current literature on in utero exposure to metformin lacks long-term clinical trials and mechanistic studies. Current literature on the effects of metformin on mature pancreatic ß-cells highlights its dual, opposing, protective, or inhibitory effects, depending on metabolic environment. However, the impact of metformin on developing human pancreatic ß-cells remains unknown. In this study, we investigated the potential effects of metformin exposure on human pancreatic ß-cell development and function in vitro. In the absence of metabolic challenges such as high levels of glucose and fatty acids, metformin exposure impaired the development and function of pancreatic ß-cells, with downregulation of pancreatic genes and dysfunctional mitochondrial respiration. It also affected the insulin secretion function of pancreatic ß-cells. These findings call for further in-depth evaluation of the exposure of human embryonic and fetal tissue during pregnancy to metformin and its implications for long-term offspring health.