Atlas of multilineage stem cell differentiation reveals TMEM88 as a developmental regulator of blood pressure
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.
Authors
- Yuliangzi Sun (ORCID: https://orcid.org/0000-0001-9785-4261)
- Meredith A. Redd (ORCID: https://orcid.org/0000-0002-4143-1726)
- Duy Pham (ORCID: https://orcid.org/0000-0002-7753-8744)
- Zezhuo Su (ORCID: https://orcid.org/0000-0001-5915-1602)
- Han Sheng Chiu (ORCID: https://orcid.org/0000-0003-2248-0845)
- Sally L. Dunwoodie (ORCID: https://orcid.org/0000-0002-2069-7349)
- Di Xia (ORCID: https://orcid.org/0000-0001-8058-5536)
- Joshua W. K. Ho (ORCID: https://orcid.org/0000-0003-2331-7011)
- Quan Nguyen (ORCID: https://orcid.org/0000-0001-7870-5703)
- Stacey B. Andersen (ORCID: https://orcid.org/0000-0002-1741-2832)
- Enakshi Sinniah (ORCID: https://orcid.org/0000-0002-3403-3658)
- Men Chee Tan (ORCID: https://orcid.org/0000-0002-7304-494X)
- Qiongyi Zhao (ORCID: https://orcid.org/0000-0002-6341-0416)
- Dalia Mizikovsky (ORCID: https://orcid.org/0000-0002-8742-963X)
- Mikael Bodén (ORCID: https://orcid.org/0000-0003-3548-268X)
- Sakurako Kobayashi
- Patrick Tam (ORCID: https://orcid.org/0000-0001-6950-8388)
- Tessa Werner (ORCID: https://orcid.org/0000-0002-7789-6816)
- Sumedha Negi (ORCID: https://orcid.org/0009-0001-7523-3576)
- Joseph E. Powell (ORCID: https://orcid.org/0000-0002-5070-4124)
- Sophie Shen (ORCID: https://orcid.org/0000-0002-1867-050X)
- Samuel W. Lukowski (ORCID: https://orcid.org/0000-0002-8598-7902)
- Jennifer E. Outhwaite (ORCID: https://orcid.org/0000-0001-9569-5973)
- Ella MMA Martin (ORCID: https://orcid.org/0000-0001-9511-9175)
- Gavin Chapman (ORCID: https://orcid.org/0000-0002-3513-723X)
- Nathan J. Palpant (ORCID: https://orcid.org/0000-0002-9334-8107)
- Woo Jun Shim (ORCID: https://orcid.org/0000-0001-9446-7821)
- Daniel Kim (ORCID: https://orcid.org/0000-0002-8405-6719)
- Xiaoli Chen (ORCID: https://orcid.org/0000-0003-0536-1553)
- Pengyi Yang (ORCID: https://orcid.org/0000-0003-1098-3138)
Institutions
- The University of Sydney (AU)
- Garvan Institute of Medical Research (AU)
- Children's Medical Research Institute (AU)
- The University of Queensland (AU)
- Victor Chang Cardiac Research Institute (AU)
- UNSW Sydney (AU)
- University of Hong Kong (HK)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-04
- DOI
- https://doi.org/10.1038/s41467-025-56533-2
- Citations
- 2
- Primary Topic
- Congenital heart defects research
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Australian Government
- National Heart Foundation of Australia
- Monash University
- Innovation and Technology Commission
- New South Wales Government
- Medical Research Council
- Australian Research Council
- National Health and Medical Research Council
- Queensland Brain Institute