Minireview: beta-cell replacement therapy for diabetes in the 21st century: manipulation of cell fate by directed differentiation

Abstract

Pancreatic beta-cell failure underlies type 1 diabetes; it also contributes in an essential way to type 2 diabetes. beta-Cell replacement is an important component of any cure for diabetes. The current options of islet and pancreas transplantation are not satisfactory as definitive forms of therapy. Here, we review strategies for induced de novo pancreatic beta-cell formation, which depend on the targeted differentiation of cells into pancreatic beta-cells. With this objective in mind, one can manipulate the fate of three different types of cells: 1) from terminally differentiated cells, e.g. exocrine pancreatic cells, into beta-cells; 2) from multipotent adult stem cells, e.g. hepatic oval cells, into pancreatic islets; and 3) from pluripotent stem cells, e.g. embryonic stem cells and induced pluripotent stem cells, into beta-cells. We will examine the pros and cons of each strategy as well as the hurdles that must be overcome before these approaches to generate new beta-cells will be ready for clinical application.

Figure 1

Schematic representation of the various pathways of reprogramming by directed differentiation. Lineage determination by targeted differentiation of pluripotent (ES and iPS) cells is represented by the green arrow. Lineage switching between progenitor cells by transdetermination is represented by the horizontal blue arrow. Lineage switching between terminally differentiated cells can occur either via dedifferentiation and redifferentiation with an intervening progenitor state (orange arrow) or via direct transdetermination (red arrow).

Figure 2

Schematic representation of transdetermination (blue arrow) of hepatic oval cells into islet progenitors. The black continuous lines represent normal differentiation and the interrupted lines the paths taken for regeneration and repair. The orange arrows signify the normal replication process of β-cells and hepatocytes.