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October 30, 2020

A single chemical produces more pancreas cells in the lab

The Osafune laboratory discovers a signaling pathway that is critical for the production of pancreatic progenitor cells.

Type 1 diabetes is an autoimmune disease in which the body kills pancreatic islet cells, the cells responsible for producing insulin. The most effective treatments include islet transplantation, but donors are rare. As a more stable source, researchers are exploring iPS cells, which can be differentiated into islet cells. In a new study seen in Cell Chemical Biology, CiRA Prof. Kenji Osafune and his research team report that the activation of non-canonical Wnt signaling through Wnt7B and the transcription factor YY1 could significantly enhance the proliferation of pancreatic progenitor cells differentiated from iPS cells.

During the differentiation of iPS cells to islet cells, the iPS cells pass through a number of cellular stages, including pancreatic progenitor cells. Pancreatic progenitor cells can undergo massive expansion and become all the cells in the adult pancreas. Thus, stem cell research on diabetes has focused on capturing these cells in the lab, since they could be used to produce a high number of islet cells for therapies.

However, Osafune stresses that there is still much to learn about how pancreatic progenitor cells develop in humans.

"Most of our knowledge comes from mouse studies. In mouse, Wnt7b promotes the proliferation of pancreatic progenitor cells through Wnt canonical signaling. Our work with human iPS cells found a non-canonical pathway. This may illustrate species differences and the importance of more study on the non-canonical pathway in pancreas development," he said.

Wnt signaling is crucial for the development of several organs and tissues, and canonical and non-canonical are distinguished by their involvement of the protein β-catenin. Moreover, Wnt molecules like Wnt7b can operate using both pathways.

The study shows that Wnt7b promotes pancreatic progenitor cell expansion through cell-cell contact and that suppressing Wnt7b activity in the progenitor cells blocks their expansion.

Additionally, the lab had previously discovered a chemical compound known as AT7867 can promote the number of pancreatic progenitor cells. Connecting that fact with the Wnt7b discovery in this study, they showed that AT7867 prevented the phosphorylation of the transcription factor YY1 to elevate Wnt7b levels.

At the same time, AT7867 had no effect on β-catenin activation, reaffirming that Wnt7b acting through the non-canonical pathway was responsible for the pancreatic progenitor cell proliferation.

"Producing pancreatic progenitor cells from stem cells in the lab requires detailed understanding of natural development including the signaling pathways involved. Previous research had put an emphasis on the Wnt canonical pathway, but our findings suggest other routes should be explored," Osafune said.

Paper Details
  • Journal: Cell Chemical Biology
  • Title: Combined omics approaches reveal the roles of non-canonical WNT7B signaling and YY1 in the proliferation of human pancreatic progenitor cells
  • Authors: Azuma Kimura1, Taro Toyoda1, Mio Iwasaki2, Ryusuke Hirama3, and Kenji Osafune1
  • Author Affiliations:
    1. Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
    2. Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
    3. Research Institute for Bioscience Products and Fine Chemicals, Ajinomoto Co., Inc. Kawasaki, Kanagawa, Japan
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