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

Abstract

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by the specific destruction of pancreatic islet β 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 β cells in the body, stem cell therapy for diabetes has attracted great attention in the academic community and the general public. Transplantation of islet β-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 β cells with complete insulin secretion in vitro is crucial. However, after much research, it has been found that the β-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 β-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 β 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 β-like cells in vitro. This article reviews β 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.

Keywords: Maturation; Stem cell therapy; Type 1 diabetes mellitus; β cell.

Figure 1

β-cell development and maturation in vivo. Important stages of β cell development and maturation in vivo, which mainly include distal foregut endoderm, pancreatic endoderm, endocrine progenitor, immature β cells, and mature β cells, and key transcription factors involved are described. GSIS: Glucose stimulated insulin secretion.

Figure 2

Relationship between mTORC1 and AMPK in the process of β cell transformation from immature to mature. Immediately after birth, the nutritional substrates are mainly amino acids, which activate the nutritionally sensitive mTORC1 and promote cell proliferation. mTORC1 is inhibited by AMPK and upstream regulatory factors TSC1/TSC2. When the nutritional substrate changes from amino acids to glucose, AMPK activity is stimulated. AMPK is activated by the upstream factor LKB1 under the regulation of intracellular ratio of ATP vs AMP/ADP, inhibits β cell proliferation, and promotes maturation, resulting in the establishment of adult-type glucose stimulated insulin secretion.

Figure 3

Paracrine regulations within the pancreatic islets. A: There are at least 5 paracrine regulatory circuits within the islets, among which α and β cells are two important cells that fine-tune the secretion of islet hormones that regulate blood glucose homeostasis. At the same time, δ and ε cells can also regulate the secretion of insulin and glucagon through the paracrine interactions. Meanwhile, the enteroendocrine hormones GLP1 and GIP secreted from the intestinal endocrine cells can also regulate β-cell insulin secretion by binding to receptors on the cell membrane; B: More detailed interactions between α and β cells.