Islet Cell Development

Abstract

Over the last years, there has been great success in driving stem cells toward insulin-expressing cells. However, the protocols developed to date have some limitations, such as low reliability and low insulin production. The most successful protocols used for generation of insulin-producing cells from stem cells mimic in vitro pancreatic organogenesis by directing the stem cells through stages that resemble several pancreatic developmental stages. Islet cell fate is coordinated by a complex network of inductive signals and regulatory transcription factors that, in a combinatorial way, determine pancreatic organ specification, differentiation, growth, and lineage. Together, these signals and factors direct the progression from multipotent progenitor cells to mature pancreatic cells. Later in development and adult life, several of these factors also contribute to maintain the differentiated phenotype of islet cells. A detailed understanding of the processes that operate in the pancreas during embryogenesis will help us to develop a suitable source of cells for diabetes therapy. In this chapter, we will discuss the main transcription factors involved in pancreas specification and beta-cell formation.

Impairment of Rat Fetal Beta-Cell Development by Maternal Exposure to Dexamethasone during Different Time-Windows

“…Later, the exo-endocrine specification is controlled by the Notch/Hes signaling system, which when active leads, in the exocrine and ductal progenitors and to the suppression of the pro-endocrine factor neurogenin-3, a transcription factor transiently expressed in pancreas, which controls the commitment of multipotent pancreatic endodermal progenitors to the endocrine fate [27], [28]. After the exo-endocrine specification, the endocrine cell differentiation is based on the successive expression of transcription factors which are different for each endocrine cell (for review see [23], [25], [29]. In addition to its early role in the pancreas development, Pdx1 reappears later and intervenes in beta-cell differentiation.…”

Regulation of pancreatic function by connective tissue growth factor (CTGF, CCN2)

“…Endocrine progenitor cells arise via notch/delta signaling in ductal epithelial cells, resulting in their delamination from the epithelium and differentiation into proliferative hormone-producing cells organized as islets [27, 28]. This developmental process, which is initiated on embryonic Day 9.5 (E9.5) in the mouse, is tightly orchestrated by a complex network of transcription factors [28, 29], including neurogenin 3 which plays a central role in specifying the endocrine component [30] (Figure 2).…”

Maintenance of β-Cell Maturity and Plasticity in the Adult Pancreas

“…The prenatal origins and development of β-cells (1,2), the molecular mechanisms of adult β-cell proliferation (3,4), and programmed β-cell death (5) have all been reviewed recently and will not be revisited here. The maintenance and adaptation of β-cell mass after birth involves the addition of new β-cells (6).…”