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April 07, 2020

Generating more pancreas cells to study diabetes

The pancreas is divided into exocrine and endocrine glands, the latter being responsible for producing several hormones including insulin and is accordingly associated with diseases like diabetes. To understand how pancreatic endocrine cells develop, the Yoshiya Kawaguchi laboratory used human iPS cells and found a previously undiscovered role for forkhead box protein O1 (FoxO1). The discovery is expected to enhance the future production of pancreatic endocrine cells for regenerative medicine and drug discovery.

To generate pancreatic endocrine cells from stem cells, scientists mix a series of chemicals that mimic the signaling factors that occur in normal pancreatogenesis. Scientists are especially interested in producing the precursor cells, since they are easier to multiply into large numbers than pancreatic endocrine cells themselves. FoxO1 is a transcription factor regulated by insulin, but it is also expressed during normal pancreas development.

The study shows that exposing the human iPS cells transiently to a FoxO1 inhibitor significantly increases the number of pancreatic endoderm cell precursors, which themselves resulted in more endocrine cells. The transient inhibition was found to promote Wnt signaling, a foundational signaling pathway in cell fate decision-making during the early stages of development. Such mutually opposing effects between FoxO1 and Wnt are known in the development of other organs and tissues including bone, cartilage and heart. The same effects were confirmed in mouse pancreatogenesis, suggesting the universality of this mechanism.

Overall, the study provides new insights on not only the signaling factors in pancreatic endocrine development but also their temporal regulation.

Paper Details
  • Journal: Stem Cell Research
  • Title: Transient FOXO1 inhibition in pancreatic endoderm promotes the generation of NGN3+ endocrine precursors from human iPSCs
  • Authors: Ben Sasaki1,2, Shinji Uemoto2, Yoshiya Kawaguchi1
  • Author Affiliations:
    1. Center for iPS cell research and application (CiRA), Kyoto University, Japan
    2. Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kyoto University Graduate School of Medicine, Kyoto University
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