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

Author

Listed:
  • 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
    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
    University of New South Wales)

  • Ella M. M. A. Martin

    (Victor Chang Cardiac Research Institute)

  • Di Xia

    (The University of Queensland
    The University of Queensland)

  • Duy Pham

    (The University of Queensland)

  • Zezhuo Su

    (Pokfulam
    Hong Kong Science Park)

  • Daniel Kim

    (University of Sydney)

  • Pengyi Yang

    (University of Sydney
    University of Sydney)

  • Men Chee Tan

    (The University of Queensland
    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
    Cellular Genomics Futures Institute)

  • Sally L. Dunwoodie

    (Victor Chang Cardiac Research Institute
    University of New South Wales
    University of New South Wales)

  • Patrick P. L. Tam

    (University of Sydney
    University of Sydney)

  • Mikael Bodén

    (The University of Queensland)

  • Joshua W. K. Ho

    (Pokfulam
    Hong Kong Science Park)

  • Quan Nguyen

    (The University of Queensland)

  • Nathan J. Palpant

    (The University of Queensland
    University of Sydney)

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.

Suggested Citation

  • 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 Cha, 2025. "Atlas of multilineage stem cell differentiation reveals TMEM88 as a developmental regulator of blood pressure," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56533-2
    DOI: 10.1038/s41467-025-56533-2
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    as
    1. Jan Kazenwadel & Parvathy Venugopal & Anna Oszmiana & John Toubia & Luis Arriola-Martinez & Virginia Panara & Sandra G. Piltz & Chris Brown & Wanshu Ma & Andreas W. Schreiber & Katarzyna Koltowska & S, 2023. "A Prox1 enhancer represses haematopoiesis in the lymphatic vasculature," Nature, Nature, vol. 614(7947), pages 343-348, February.
    2. Chengxiang Qiu & Beth K. Martin & Ian C. Welsh & Riza M. Daza & Truc-Mai Le & Xingfan Huang & Eva K. Nichols & Megan L. Taylor & Olivia Fulton & Diana R. O’Day & Anne Roshella Gomes & Saskia Ilcisin &, 2024. "A single-cell time-lapse of mouse prenatal development from gastrula to birth," Nature, Nature, vol. 626(8001), pages 1084-1093, February.
    3. Ayshwarya Subramanian & Eriene-Heidi Sidhom & Maheswarareddy Emani & Katherine Vernon & Nareh Sahakian & Yiming Zhou & Maria Kost-Alimova & Michal Slyper & Julia Waldman & Danielle Dionne & Lan T. Ngu, 2019. "Single cell census of human kidney organoids shows reproducibility and diminished off-target cells after transplantation," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    4. Suoqin Jin & Christian F. Guerrero-Juarez & Lihua Zhang & Ivan Chang & Raul Ramos & Chen-Hsiang Kuan & Peggy Myung & Maksim V. Plikus & Qing Nie, 2021. "Inference and analysis of cell-cell communication using CellChat," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    5. Brent A. Biddy & Wenjun Kong & Kenji Kamimoto & Chuner Guo & Sarah E. Waye & Tao Sun & Samantha A. Morris, 2018. "Single-cell mapping of lineage and identity in direct reprogramming," Nature, Nature, vol. 564(7735), pages 219-224, December.
    6. Blanca Pijuan-Sala & Jonathan A. Griffiths & Carolina Guibentif & Tom W. Hiscock & Wajid Jawaid & Fernando J. Calero-Nieto & Carla Mulas & Ximena Ibarra-Soria & Richard C. V. Tyser & Debbie Lee Lian H, 2019. "A single-cell molecular map of mouse gastrulation and early organogenesis," Nature, Nature, vol. 566(7745), pages 490-495, February.
    7. Guangdun Peng & Shengbao Suo & Guizhong Cui & Fang Yu & Ran Wang & Jun Chen & Shirui Chen & Zhiwen Liu & Guoyu Chen & Yun Qian & Patrick P. L. Tam & Jing-Dong J. Han & Naihe Jing, 2019. "Molecular architecture of lineage allocation and tissue organization in early mouse embryo," Nature, Nature, vol. 572(7770), pages 528-532, August.
    8. Anshul Kundaje & Wouter Meuleman & Jason Ernst & Misha Bilenky & Angela Yen & Alireza Heravi-Moussavi & Pouya Kheradpour & Zhizhuo Zhang & Jianrong Wang & Michael J. Ziller & Viren Amin & John W. Whit, 2015. "Integrative analysis of 111 reference human epigenomes," Nature, Nature, vol. 518(7539), pages 317-330, February.
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