Endodermal Development & Differentiation

Dr. Ray Dunn and group members transferred to the Skin Research Institute of Singapore on the 1st May 2020.

In life, a single embryonic stem cell gives rise to all the 220 or so specialized cell types that make up the human body. Amongst these, some stem cells will turn into the critical insulin-producing cells of the pancreas, whose loss of function leads to diabetes. Ray's group is investigating how one can mimic this process, starting with cultured human stem cells to generate safe and efficient insulin-producing cells for the treatment of diabetes.

Type I diabetes, which accounts for 5 to 10% of all diagnosed cases, is caused by the autoimmune destruction of the pancreatic beta cells that produce insulin. The focal nature of this pathology makes diabetes an ideal candidate disease for the development of cell replacement therapies. Indeed, recent advances in clinical islet transplantation that draw upon improved islet isolation techniques and immunosuppression regimes, the so-called Edmonton protocol, have been very successful at keeping patients free from insulin dependency for extended, though not indefinite, periods of time. However, the limited supply of donor pancreatic tissue makes this cell therapy approach inadequate to meet the global patient demand for treatment. Intensive research has thus focused on identifying alternative sources of beta cells, of which human embryonic stem cells (hESC) are an appealing choice. By analogy to the behavior of mouse ES cells and given the appropriate culture conditions, hESC can probably form the approximately 220 specialized cell types that comprise the adult human.

In our group, we aim to harness this remarkable lineage potential to generate clinically compliant, functional beta cells that may provide an inexhaustible supply of material for the treatment of type I diabetes. In practice, our experimental design is largely guided by our understanding of mammalian definitive endoderm formation and the inductive interactions and morphogenesis that underlie the emergence of one of its derivatives, the pancreas. At present, we are focusing on the development of a 2D (or "monolayer") protocol that promotes the efficient formation of beta-like cells from hESC after approximately three weeks of in vitro differentiation. In addition, we have embarked on several discovery based strategies including a small molecule library screen to identify factors/pathways that promote beta-cell formation as well as ChIP-on-CHIP and transcriptional profiling studies to reveal novel genes that regulate endoderm formation and specification of early pancreatic progenitors. Lastly, we anticipate building on the groups' strengths in mouse ES cell culture and genetics to validate targets that emerge from these hESC based approaches.