Robust differentiation of purified islet progenitors into functional beta-like cells for diabetes cell therapy — ASN Events

Robust differentiation of purified islet progenitors into functional beta-like cells for diabetes cell therapy (#109)

Fang-Xu Jiang 1 , Kevin Li 1 , Emma Jamieson 1 , Adrian Charles 1 , Jan Dickinson 1 , Masahito Matsumoto 2 , Grant Morahan 1 , Mike Archer 1
  1. University of Western Australia, Perth, WA, Australia
  2. Department of Molecular Biology, Saitama Medical School, Saitama, Japan

The ultimate goal in regenerative medicine is to generate fully-differentiated functional cells. Despite the pivotal importance in a replacement cell therapy for type 1 diabetes and some forms of type 2 diabetes, functional insulin-secreting β cells have not yet been directly differentiated from any defined stem cells including pancreatic/islet progenitors. We report here that purified genetically-tagged mouse neurogenin 3-expressing cells, progenitors of all islet lineages, very effectively gave rise to glucose-responsive insulin-producing cells in a unique direct differentiation (DD) system. After as short as 4-6 days of DD, the differentiated β-like cells exhibited many features of mature β cells including expressing a wide range of genes for transcription factors, hormones, posttranscription modification and glucose sensing, performing glucose-stimulated insulin secretion as well as having specific electron dense insulin granules. Transplantation of these insulin-secreting cells ameliorated streptozotocin-induced hyperglycemia. Furthermore, screening from 61 potential maturation factors, we identified a single molecule which converted the β-like cells to be completely glucose-responsive. Remarkably, enriched human islet progenitors gave rise effectively to insulin-producing cells in the same DD condition. The ability to generate functional insulin-secreting cells from DD of islet progenitors provides novel insights into islet developmental biology and has important implications for the regenerative therapy for diabetes mellitus.

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