Formation and regeneration of the endocrine pancreas

Abstract

The elaboration of the pancreas from epithelial buds to the intricate organ requires complex patterning information that controls fundamental cellular processes such as differentiation and proliferation of pancreatic progenitor cells. During pancreatic organogenesis, endocrine cells are generated from a population of pancreatic progenitor cells. The progenitor cells during the early development simultaneously receive multiple signals, some mitogenic and some inducing differentiation. These extrinsic signals are interpreted through an intrinsic mechanism that either commits the progenitor cell to the mitotic cell cycle or leads to exit from the cell cycle in order to differentiate. The endocrine cells that differentiate from progenitor cells are postmitotic, and direct lineage tracing analyses indicate that a population of progenitor cells persists throughout embryogenesis to allow the differentiation of new endocrine cells. At the end of embryogenesis an early postnatal period is characterized by high rates of beta cell proliferation leading to massive increases in beta cell mass. The beta cell mass expansion considerably slows down in adult animals, though variations in insulin demand due to physiological and pathological states such as pregnancy and obesity can lead to adaptive changes in the beta cells that include hyperplasia, hypertrophy, and increased insulin synthesis and secretion. Deciphering the mechanisms that regulate the plasticity of beta cell mass can be an important step in developing effective strategies to treat diabetes.

Figure 1

The decision to proliferate or differentiate. Pdx1+ progenitor cells face a binary decision to either self-renew to expand the progenitor pool, or to undergo cell cycle arrest and begin the differentiation process. Progenitor cells that receive the Notch signal pathway via downstream effector Hes1 represses not only genes specific to differentiation but also the cell cycle arrest mediator, p57, thereby allowing the progenitor cells to continue to self-renew. Cells that do not receive the Notch signal upregulate p57 and exit the cell cycle to allow the differentiation process. The quiescent state of differentiated cell type is maintained by accumulation of cell cycle inhibitor p27.

Figure 2

The proliferative capacity of beta cells changes during the progression from embryogenesis through adulthood. During early embryogenesis, beta cell umbers are established by direct differentiation from Pdx1+ progenitor cells. In late gestation through the neonatal stages of life, the beta cell population is expanded through high rates of proliferation in existing beta cells. In adulthood, low levels of beta cell replication maintain a constant set of beta cells ready to provide insulin to meet metabolic demand.

Figure 3

The inability of beta cell mass to adaptively expand in order to compensate for increased insulin demand leads to diabetes. When either pregnancy- or obesity–related insulin resistance creates an increase in metabolic demand for insulin, healthy beta cells are able to expand in number and size to compensate for increased metabolic need for insulin, thereby maintaining glucose homeostasis. When beta cells to expand and adapt to changing metabolic demand, the reduced insulin secretion results in hyperglycemia.