On the origin of the beta cell

Abstract

The major forms of diabetes are characterized by pancreatic islet beta-cell dysfunction and decreased beta-cell numbers, raising hope for cell replacement therapy. Although human islet transplantation is a cell-based therapy under clinical investigation for the treatment of type 1 diabetes, the limited availability of human cadaveric islets for transplantation will preclude its widespread therapeutic application. The result has been an intense focus on the development of alternate sources of beta cells, such as through the guided differentiation of stem or precursor cell populations or the transdifferentiation of more plentiful mature cell populations. Realizing the potential for cell-based therapies, however, requires a thorough understanding of pancreas development and beta-cell formation. Pancreas development is coordinated by a complex interplay of signaling pathways and transcription factors that determine early pancreatic specification as well as the later differentiation of exocrine and endocrine lineages. This review describes the current knowledge of these factors as they relate specifically to the emergence of endocrine beta cells from pancreatic endoderm. Current therapeutic efforts to generate insulin-producing beta-like cells from embryonic stem cells have already capitalized on recent advances in our understanding of the embryonic signals and transcription factors that dictate lineage specification and will most certainly be further enhanced by a continuing emphasis on the identification of novel factors and regulatory relationships.

Figure 1.

Overview of mouse pancreatic organogenesis. Drawing depicts mouse embryonic development from early primitive streak stage (E7) through endoderm migration and specification, pancreatic budding, branching morphogenesis, and differentiation of pancreatic lineages. Multipotent progenitors that give rise to all pancreatic lineages express Pdx1, Ptf1a, CPA, and cMyc in early pancreas development, while exocrine progenitors express CPA during mid-pancreatic development. At all stages, endocrine progenitors express Ngn3.

Figure 2.

Transcription factor profile during stages of β cell formation from endodermal derivatives. Diagram indicates transcription factors expressed at each stage of differentiation. Factors initially expressed at a particular stage are color-coded as follows: gut endoderm (purple), pancreatic endoderm progenitor (blue), early endocrine progenitor (black), endocrine progenitor (orange), β cell (red).

Figure 3.

Regulation of endocrine progenitor marker Ngn3. Schematic depicts the factors and pathways within the epithelium and the mesenchyme that regulate Ngn3 expression. Large arrows indicate regulation that has been demonstrated by in vivo mouse models, while small arrows denote regulation supported by cell culture and in vitro evidence.

Figure 4.

Differentiation of β-like cells from human ES cells. Diagrams depicts protocols used by D'Amour et al. (2006) (A) and Kroon et al. (2008) (B). Exogenous factors added to induce differentiation into particular lineages are indicated above, and transcription factors expressed at each stage are denoted in italics below. Differences between the protocols are indicated in red. Adapted by permission from Macmillan Publishers Ltd.: (Nature Biotechnology, http://www.nature.com/nbt) from D'Amour et al. (2006) (© 2006) (A) and Kroon et al. (2008) (© 2008) (B).