Further Development 20.5: Defining the Factors for β Cell Differentiation by iPSC

The Endoderm: Tubes and Organs for Digestion and Respiration

In order to development a method to convert iPSCs into β cells, knowledge of the paracrine factors involved and their inhibitors was crucial. These factors were then used to transform iPSC cells into endoderm cells, which were then transformed sequentially into primitive foregut cells, pancreatic progenitor cells, endocrine progenitor cells, and finally mature insulin-secreting pancreatic β cells (Figure 1). Not only did these cells look like normal pancreatic β cells and have the same transcription factor activation pattern, they also secreted insulin upon stimulation with glucose. When injected into mice, they regulated glucose levels just like normal pancreatic β cells.

These results still don’t provide a “cure” for human diabetes, however. Human type 1 diabetes is an autoimmune disease wherein the person makes antibodies that destroy his or her own β cells, and newly generated β cells would still be prone to this destruction. However, because induced β cells can now be grown by the millions, they may provide a palliative therapy until we find a way to block the autoimmune destruction of β cells. The goal would be to have the induced β cells remain in the person throughout their life.

**Figure 1** Production of functional insulin-secreting human β cells from adult cells. The adult skin cell is converted into an induced pluripotent stem cell (iPSC) by the transcription factors mentioned in Chapter 5. The iPSC can become almost any cell in the embryo. To make the cell into a pancreatic β cell, researchers sequentially mimicked the conditions seen in the embryo. This meant providing it certain paracrine factors and paracrine factor inhibitors. The iPSC first became a cell type having the transcription factor pattern of primitive endoderm. Then it became sequentially, like a foregut cell, a pancreatic cell, a pancreatic endocrine cell, and finally (after some intermediary steps not shown here), a pancreatic β cell. These β cells could be transferred into mice, where they were able to regulate glucose levels and cure the mouse model of diabetes. (After Pagliuca et al. 2014; Rezania et al. 2014.)