Epigenetics, cell cycle and stem cell metabolism. Formation of insulin-producing cells

Abstract

Stem cell (SC) differentiation requires a series of chromatin rearrangements to establish cell identity. Posttranslational modifications of histones usually regulate the dynamics of heterochromatin. Histones are subjected to various modifications, such as acetylation, methylation, phosphorylation and ubiquinination, and thus contribute to regulation of chromatin status and transcriptional activity. The chemically stable pattern of methylated histones promotes cellular memory relative to external stimuli, maintaining transcription levels of adaptive genes even after elimination of environmental signals. Chromatin modifications play an important role in the maturation of pancreatic islet cells, the establishment of a secretion pattern that stimulates the regulation of insulin secretion. MicroRNAs, a class of endogenous small noncoding RNAs in eukaryotes, are important regulators of gene expression at the level of posttranscriptional mechanisms. MicroRNAs regulate insulin secretion, pancreatic development, and β-cell differentiation. Pluripotent SCs are characterized by a high rate of proliferation, the ability to self-repair and the potential for differentiation in different cell types. This rapid proliferation is due to a modified cell cycle that allows cells to rapidly transition from DNA synthesis to cell division by reducing the time of gap (G1 and G2) phases. The canonical WNT/β-catenin signaling pathway is characterized as a major driver of cell growth and proliferation. At G1, WNT signaling induces a transition to the S-phase. Compared to their somatic counterparts, pluripotent SCs exhibit a high rate of glycolysis similar to aerobic glycolysis in cancer cells, a phenomenon known as the Warburg effect, which is important for maintaining SC properties. In stem cells, the extracellular influx of Ca2+ into the cytoplasm is mediated mainly by depot-controlled Ca2+ channels. Extracellular calcium has been shown to promote SC proliferation and thus may be involved in transplant therapy.