Individuals with type 1 diabetes are unable to regulate blood glucose because their insulin-secreting pancreatic beta cells have been destroyed by the immune system. Studies suggest that replacing these lost cells with stem cell-derived beta cells might reverse this effect. However, reproducible methods for generating large populations of stem cell-derived beta cells are currently lacking because the complex pathways that control pancreatic cell development are not well defined.

A new study led by McEwen Centre Researcher Dr. Maria Cristina Nostro has advanced this area of research by revealing key pathways that regulate the differentiation of human pluripotent stem cell (hPSC)-derived pancreatic progenitor cells.

Previous studies by Dr. Nostro provided a protocol for the generation of hPSC-derived pancreatic progenitors that is dependent on treatment with key growth factors such as retinoic acid and fibroblast growth factor 10, as well as inhibition of bone morphogenetic protein (BMP) and hedgehog signalling pathways. Treatment of these progenitors with inhibitors of TGFβ signalling leads to the generation of cells that lack NKX6-1 expression and are non-glucose responsive.

Dr. Nostro’s current study revealed that activation of the epidermal growth factor and nicotinamide signalling pathways generates NKX6-1⁺ cells that have the potential to differentiate into beta-like cells in vivo. Importantly, the study revealed that the size of the NKX6-1⁺ population is affected by the duration of treatment with retinoic acid and fibroblast growth factor 10, as well as treatment with the inhibitors of BMP and hedgehog signalling pathways.

These key findings define—for the first time—the pathways that regulate the development of NKX6-1⁺ progenitors. They also provide a strategy for generating highly enriched populations of these cells, which can be used to uncover the pathways that regulate the maturation of hPSC-derived beta cell progenitors into functional pancreatic beta cells.

This work was supported by the National Health and Medical Research Council of Australia, the Juvenile Diabetes Research Foundation, Stem Cells Australia and the Victorian Government's Operational Infrastructure Support Program and the Toronto General & Western Foundation. G Keller holds a Tier 1 Canada Research Chair in Embryonic Stem Cell Biology and MC Nostro is the McEwen Centre for Regenerative Medicine Harry Rosen Chair in Diabetes and Regenerative Medicine Research. Image courtesy of MC Nostro.

Efficient generation of NKX6-1⁺ pancreatic progenitors from multiple human pluripotent stem cell lines. Nostro MC, Sarangi F, Yang C, Holland A, Elefanty AG, Stanley EG, Greiner DL, Keller G. Stem Cell Reports. 2015 Apr 1. [Abstract]

Congratulations to Dr. Andras Nagy on the successful renewal of his Tier I Canada Research Chair in Stem Cells and Regeneration. The award will support Dr. Nagy’s research, which aims to improve our understanding of human development by uncovering the pathways that regulate pluripotency and stem cell self-renewal.

The University of Toronto’s Department of Chemical Engineering & Applied Chemistry, in partnership with the Institute of Biomaterials & Biomedical Engineering, will be hosting a symposium to honour Dr. Molly Shoichet’s appointment to the rank of University Professor on Thursday June 4th.  A host of experts, including Drs. Cindi Morshead (University of Toronto), Kevin Healy (University of California, Berkley) and Jeff Karp (Harvard Medical School), will present their research on new innovations in bioengineering and regenerative medicine at the event. The symposium will culminate with a presentation by Dr. Shoichet titled ‘Imagination and innovation: biomimetic hydrogels for 3D cell culture’. For more information on this event, click here.