Sharon N, Vanderhooft J, Straubhaar J, Mueller J, Chawla R, Zhou Q, Engquist EN, Trapnell C, Gifford DK, Melton DA. 2019. Wnt Signaling Separates the Progenitor and Endocrine Compartments during Pancreas Development. Cell reports. 27(8):2281-2291.e5. Pubmed: 31116975


In vitro differentiation of pluripotent cells into β cells is a promising alternative to cadaveric-islet transplantation as a cure for type 1 diabetes (T1D). During the directed differentiation of human embryonic stem cells (hESCS) by exogenous factors, numerous genes that affect the differentiation process are turned on and off autonomously. Manipulating these reactions could increase the efficiency of differentiation and provide a more complete control over the final composition of cell populations. To uncover in vitro autonomous responses, we performed single-cell RNA sequencing on hESCs as they differentiate in spherical clusters. We observed that endocrine cells and their progenitors exist beside one another in separate compartments that activate distinct genetic pathways. WNT pathway inhibition in the endocrine domain of the differentiating clusters reveals a necessary role for the WNT inhibitor APC during islet formation in vivo. Accordingly, WNT inhibition in vitro causes an increase in the proportion of differentiated endocrine cells.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

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Doug Melton is pursuing a cure for type 1 diabetes. His lab studies the developmental biology of the pancreas, using that information to grow and develop pancreatic cells (islets of Langerhans). In parallel, they investigate ways to protect beta cells from autoimmune attack.

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