Atlas of multilineage stem cell differentiation reveals TMEM88 as a developmental regulator of blood pressure
Abstract
Abstract Pluripotent stem cells provide a scalable approach to analyse molecular regulation of cell differentiation across developmental lineages. Here, we engineer barcoded induced pluripotent stem cells to generate an atlas of multilineage differentiation from pluripotency, encompassing an eight-day time course with modulation of WNT, BMP, and VEGF signalling pathways. Annotation of in vitro cell types with reference to in vivo development reveals diverse mesendoderm lineage cell types including lateral plate and paraxial mesoderm, neural crest, and primitive gut. Interrogation of temporal and signalling-specific gene expression in this atlas, evaluated against cell type-specific gene expression in human complex trait data highlights the WNT-inhibitor gene TMEM88 as a regulator of mesendodermal lineages influencing cardiovascular and anthropometric traits. Genetic TMEM88 loss of function models show impaired differentiation of endodermal and mesodermal derivatives in vitro and dysregulated arterial blood pressure in vivo. Together, this study provides an atlas of multilineage stem cell differentiation and analysis pipelines to dissect genetic determinants of mammalian developmental physiology.
Article Details
Authors (30)
Sophie Shen
Tessa Werner
Samuel W. Lukowski
Stacey Andersen
Yuliangzi Sun
Woo Jun Shim
Dalia Mizikovsky
Sakurako Kobayashi
Jennifer Outhwaite
Han Sheng Chiu
Xiaoli Chen
Gavin Chapman
Ella M. M. A. Martin
Di Xia
Duy Pham
Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
Zezhuo Su
Daniel Kim
Pengyi Yang
Men Chee Tan
Enakshi Sinniah
Qiongyi Zhao
Sumedha Negi
Meredith A. Redd
Joseph E. Powell
Sally L. Dunwoodie
Patrick P. L. Tam
Embryology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, University of Sydney
Mikael Bodén
Joshua W. K. Ho
Quan Nguyen
Princeton University
Nathan J. Palpant
Institute for Molecular Bioscience, The University of Queensland