Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia
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Efficient Generation of Pancreas/Duodenum Homeobox Protein 1+ Posterior Foregut/Pancreatic Progenitors from hPSCs in Adhesion Cultures
Published on: March 27, 2019
Adrian Kee Keong Teo1, Hwee Hui Lau2, Ivan Achel Valdez3
1Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Stem Cell Institute, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA; Discovery Research Division, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos #06-07, Singapore 138673, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore.
Abstract:
Patients with an HNF1B(S148L/+) mutation (MODY5) typically exhibit pancreatic hypoplasia. However, the molecular mechanisms are unknown due to inaccessibility of patient material and because mouse models do not fully recapitulate MODY5. Here, we differentiated MODY5 human-induced pluripotent stem cells (hiPSCs) into pancreatic progenitors, and show that the HNF1B(S148L/+) mutation causes a compensatory increase in several pancreatic transcription factors, and surprisingly, a decrease in PAX6 pancreatic gene expression. The lack of suppression of PDX1, PTF1A, GATA4, and GATA6 indicates that MODY5-mediated pancreatic hypoplasia is mechanistically independent. Overexpression studies demonstrate that a compensatory increase in PDX1 gene expression is due to mutant HNF1B(S148L/+) but not wild-type HNF1B or HNF1A. Furthermore, HNF1B does not appear to directly regulate PAX6 gene expression necessary for glucose tolerance. Our results demonstrate compensatory mechanisms in the pancreatic transcription factor network due to mutant HNF1B(S148L/+) protein. Thus, patients typically develop MODY5 but not neonatal diabetes despite exhibiting pancreatic hypoplasia.
