Epithelial cells, which line the surfaces of blood vessels and organs, possess a feature called apicobasal polarity that enables them to distinguish between their exterior and interior environment by using domains – apical (for the exterior) and basal (for the interior) – in the plasma membrane. This ability is a pre-requisite for such cells to perform fundamental biological roles, such as regulating epithelial development or differentiation (the ability to change into other cell types). While there is a known link between, for example, apical polarity and epithelial differentiation, how this process is regulated is still not understood.

Using the developing mouse pancreas as a model, a team from the University of Copenhagen and Vanderbilt University aimed to decipher the role of apical polarity in differentiation and cell fate (Nature Cell Biology 19 1313). They found that epidermal growth factor receptor (EGFR) signalling is key to controlling polarity changes in the mouse pancreas and that, importantly, the same applies to human stem cells. These findings pave the way for the use of human stem cells to transform into insulin-producing cells and, ultimately, the development of stem cell therapies for patients suffering from diabetes.

Progenitor cells (the ones that transform into hormone-producing endocrine cells) express the transcription factor neurogenin3⁺ (Ngn3⁺), which is necessary for differentiation into endocrine cells during pancreatic development. Considering the expression level of Ngn3⁺, where cells can be either Ngn3^High or Ngn3^Low, the authors decided to investigate the link between Ngn3⁺ cells, apical polarity and epithelial development, together with the influence of EGFR signalling.

Influences on endocrine commitment

Ngn3^Low cells have a larger apical domain and are the ones that change into β-cells. Such β-cells produce, store and release insulin, a critical regulator of glucose metabolism, which is an important factor in diabetes.

Rac1, a protein known to regulate polarity, is involved in apical domain size reduction in Ngn3^Low cells during β-cell commitment. Without Rac1, the Ngn3^Low cells tend to develop into Sox9⁺ pancreatic duct cells, the ones that secrete bicarbonate that neutralizes stomach acidity.

Phosphoinositide 3-kinase, or PI(3)K, is another protein involved in increasing the expression of Ngn3⁺ via apical domain reduction. Unsurprisingly, when the authors inhibited EGFR signalling, they observed a reduced expression of PI(3)K and Rac1, together with a reduction in β-cell differentiation.

Changing human NGN3⁺ cells into β-cells

The highlight of this study is that the mechanism underlying how EGFR signalling regulates β-cell commitment via apical polarity is the same in human NGN3⁺ cells. This means that in the human embryonic stem cell-derived NGN3⁺ cells, EGFR signalling inhibits apical polarity through the activation of RAC1 and PI(3)K.

As EGFR signalling directly controls both epithelial development and cell differentiation, by modulating apical polarity, this makes it possible to control the conversion of progenitor cells into β-cells by altering their polarity. Further study of human NGN3⁺ cells may pave the way for new stem cell therapies for patients suffering from diabetes.