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Bulk cell density and Wnt/TGFbeta signalling regulate mesendodermal patterning of human pluripotent stem cells

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  • Henning Kempf

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
    REBIRTH-Cluster of Excellence, Hannover Medical School)

  • Ruth Olmer

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
    REBIRTH-Cluster of Excellence, Hannover Medical School
    Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL))

  • Alexandra Haase

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
    REBIRTH-Cluster of Excellence, Hannover Medical School)

  • Annika Franke

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
    REBIRTH-Cluster of Excellence, Hannover Medical School)

  • Emiliano Bolesani

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
    REBIRTH-Cluster of Excellence, Hannover Medical School)

  • Kristin Schwanke

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
    REBIRTH-Cluster of Excellence, Hannover Medical School)

  • Diana Robles-Diaz

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
    REBIRTH-Cluster of Excellence, Hannover Medical School)

  • Michelle Coffee

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
    REBIRTH-Cluster of Excellence, Hannover Medical School)

  • Gudrun Göhring

    (REBIRTH-Cluster of Excellence, Hannover Medical School
    Institute of Human Genetics, Hannover Medical School)

  • Gerald Dräger

    (REBIRTH-Cluster of Excellence, Hannover Medical School
    Institute of Organic Chemistry, Leibniz University Hannover
    Center of Biomolecular Drug Research (BMWZ), Leibniz University Hannover)

  • Oliver Pötz

    (Natural and Medical Sciences Institute at the University of Tuebingen (NMI))

  • Thomas Joos

    (Natural and Medical Sciences Institute at the University of Tuebingen (NMI))

  • Erik Martinez-Hackert

    (Michigan State University)

  • Axel Haverich

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
    REBIRTH-Cluster of Excellence, Hannover Medical School)

  • Falk F. R. Buettner

    (REBIRTH-Cluster of Excellence, Hannover Medical School
    Institute for Cellular Chemistry, Hannover Medical School)

  • Ulrich Martin

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
    REBIRTH-Cluster of Excellence, Hannover Medical School
    Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL))

  • Robert Zweigerdt

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
    REBIRTH-Cluster of Excellence, Hannover Medical School)

Abstract

In vitro differentiation of human pluripotent stem cells (hPSCs) recapitulates early aspects of human embryogenesis, but the underlying processes are poorly understood and controlled. Here we show that modulating the bulk cell density (BCD: cell number per culture volume) deterministically alters anteroposterior patterning of primitive streak (PS)-like priming. The BCD in conjunction with the chemical WNT pathway activator CHIR99021 results in distinct paracrine microenvironments codifying hPSCs towards definitive endoderm, precardiac or presomitic mesoderm within the first 24 h of differentiation, respectively. Global gene expression and secretome analysis reveals that TGFß superfamily members, antagonist of Nodal signalling LEFTY1 and CER1, are paracrine determinants restricting PS progression. These data result in a tangible model disclosing how hPSC-released factors deflect CHIR99021-induced lineage commitment over time. By demonstrating a decisive, functional role of the BCD, we show its utility as a method to control lineage-specific differentiation. Furthermore, these findings have profound consequences for inter-experimental comparability, reproducibility, bioprocess optimization and scale-up.

Suggested Citation

  • Henning Kempf & Ruth Olmer & Alexandra Haase & Annika Franke & Emiliano Bolesani & Kristin Schwanke & Diana Robles-Diaz & Michelle Coffee & Gudrun Göhring & Gerald Dräger & Oliver Pötz & Thomas Joos &, 2016. "Bulk cell density and Wnt/TGFbeta signalling regulate mesendodermal patterning of human pluripotent stem cells," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13602
    DOI: 10.1038/ncomms13602
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    Cited by:

    1. Mariana A. Branco & Tiago P. Dias & Joaquim M. S. Cabral & Perpetua Pinto-do-Ó & Maria Margarida Diogo, 2022. "Human multilineage pro-epicardium/foregut organoids support the development of an epicardium/myocardium organoid," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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