β-Cell Maturation and Identity in Health and Disease

Abstract

The exponential increase of patients with diabetes mellitus urges for novel therapeutic strategies to reduce the socioeconomic burden of this disease. The loss or dysfunction of insulin-producing β-cells, in patients with type 1 and type 2 diabetes respectively, put these cells at the center of the disease initiation and progression. Therefore, major efforts have been taken to restore the β-cell mass by cell-replacement or regeneration approaches. Implementing novel therapies requires deciphering the developmental mechanisms that generate β-cells and determine the acquisition of their physiological phenotype. In this review, we summarize the current understanding of the mechanisms that coordinate the postnatal maturation of β-cells and define their functional identity. Furthermore, we discuss different routes by which β-cells lose their features and functionality in type 1 and 2 diabetic conditions. We then focus on potential mechanisms to restore the functionality of those β-cell populations that have lost their functional phenotype. Finally, we discuss the recent progress and remaining challenges facing the generation of functional mature β-cells from stem cells for cell-replacement therapy for diabetes treatment.

Keywords: SC-β-cells; dedifferentiation; diabetes; dysfunction; identity; maturation; postnatal; senescence; transdifferentiation; β-cell.

Figure 1

Pivotal TFs regulating β-cell differentiation and maturation in rodents. Schematic representation of the most prominent TFs involved in endocrine induction, lineage specification, differentiation and maturation of β-cells. Gradient colors represent the expression levels during the process. Green colored lines indicate the TFs that are transiently expressed, while the blue ones are those that remain expressed also in adulthood.

Figure 2

β-cell maturation process. Simplified representation of the complex group of events leading to the β-cell maturation in rodents. In the top part of the figure, β-cells in their immature ad mature stages, characterized by key signaling pathways. Between the two cells, the prominent TFs and markers that are differentially regulated in the maturation process are shown. Below the two most significant capacities are mentioned, proliferation for immature β-cells and GSIS for mature β-cells. Following, the type of metabolisms affecting the maturation stages are mentioned. At the bottom, the timeline of the β-cell maturation process is indicated.

Figure 3

Altered β-cell phenotypes in diabetes. Schematic representation of β-cell described phenotypes as a response to diabetic environments. On the left side, a healthy mature β-cell is shown, in the middle box, disease stressors that induce changes in β-cell phenotype are mentioned, on the right side, summary of the three β-cell phenotypes observed in diabetes: immature/dedifferentiated, transdifferentiated and senescent, with each of the different phenotypes depicting the up- or down-regulation of key markers.