Atlas of multilineage stem cell differentiation reveals TMEM88 as a developmental regulator of blood pressure

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, 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, Mikael Bodén, Joshua W. K. Ho, Quan Nguyen and Nathan J. Palpant ()
Additional contact information
Sophie Shen: The University of Queensland
Tessa Werner: The University of Queensland
Samuel W. Lukowski: The University of Queensland
Stacey Andersen: The University of Queensland
Yuliangzi Sun: The University of Queensland
Woo Jun Shim: The University of Queensland
Dalia Mizikovsky: The University of Queensland
Sakurako Kobayashi: The University of Queensland
Jennifer Outhwaite: The University of Queensland
Han Sheng Chiu: The University of Queensland
Xiaoli Chen: The University of Queensland
Gavin Chapman: Victor Chang Cardiac Research Institute
Ella M. M. A. Martin: Victor Chang Cardiac Research Institute
Di Xia: The University of Queensland
Duy Pham: The University of Queensland
Zezhuo Su: Pokfulam
Daniel Kim: University of Sydney
Pengyi Yang: University of Sydney
Men Chee Tan: The University of Queensland
Enakshi Sinniah: The University of Queensland
Qiongyi Zhao: The University of Queensland
Sumedha Negi: The University of Queensland
Meredith A. Redd: The University of Queensland
Joseph E. Powell: Garvan Institute of Medical Research
Sally L. Dunwoodie: Victor Chang Cardiac Research Institute
Patrick P. L. Tam: University of Sydney
Mikael Bodén: The University of Queensland
Joshua W. K. Ho: Pokfulam
Quan Nguyen: The University of Queensland
Nathan J. Palpant: The University of Queensland

Nature Communications, 2025, vol. 16, issue 1, 1-19

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.

Date: 2025
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DOI: 10.1038/s41467-025-56533-2

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