Functional maturation of immature β cells: A roadblock for stem cell therapy for type 1 diabetes

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by the specific destruction of pancreatic islet beta cells and is characterized as the absolute insufficiency of insulin secretion. Current insulin replacement therapy supplies insulin in a non-physiological way and is associated with devastating complications. Experimental islet transplantation therapy has been proven to restore glucose homeostasis in people with severe T1DM. However, it is restricted by many factors such as severe shortage of donor sources, progressive loss of donor cells, high cost, etc. As pluripotent stem cells have the potential to give rise to all cells including islet beta cells in the body, stem cell therapy for diabetes has attracted great attention in the academic community and the general public. Transplantation of islet beta-like cells differentiated from human pluripotent stem cells (hPSCs) has the potential to be an excellent alternative to islet transplantation. In stem cell therapy, obtaining beta cells with complete insulin secretion in vitro is crucial. However, after much research, it has been found that the beta-like cells obtained by in vitro differentiation still have many defects, including lack of adult-type glucose stimulated insulin secretion, and multi-hormonal secretion, suggesting that in vitro culture does not allows for obtaining fully mature beta-like cells for transplantation. A large number of studies have found that many transcription factors play important roles in the process of transforming immature to mature human islet beta cells. Furthermore, PDX1, NKX6.1, SOX9, NGN3, PAX4, etc., are important in inducing hPSC differentiation in vitro. The absent or deficient expression of any of these key factors may lead to the islet development defect in vivo and the failure of stem cells to differentiate into genuine functional beta-like cells in vitro. This article reviews beta cell maturation in vivo and in vitro and the vital roles of key molecules in this process, in order to explore the current problems in stem cell therapy for diabetes.

Automated summary

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease that involves the destruction of pancreatic islet beta cells and results in insulin insufficiency. Although islet transplantation therapy has shown potential for restoring glucose homeostasis in severe T1DM patients, it is limited by factors such as donor shortage and cell loss. Stem cell therapy, specifically differentiating beta-like cells from human pluripotent stem cells (hPSCs), has emerged as a promising alternative, but challenges remain in obtaining fully mature and functional beta-like cells for transplantation. Various transcription factors play crucial roles in the differentiation of hPSCs into mature human islet beta cells, and deficiencies in key factors may hinder successful differentiation and islet development in vivo. Efforts are ongoing to address the current obstacles in stem cell therapy for diabetes through understanding beta cell maturation both in vivo and in vitro.