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

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, Erik Martinez-Hackert, Axel Haverich, Falk F. R. Buettner, Ulrich Martin and Robert Zweigerdt ()
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Henning Kempf: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
Ruth Olmer: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
Alexandra Haase: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
Annika Franke: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
Emiliano Bolesani: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
Kristin Schwanke: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
Diana Robles-Diaz: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
Michelle Coffee: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
Gudrun Göhring: REBIRTH-Cluster of Excellence, Hannover Medical School
Gerald Dräger: REBIRTH-Cluster of Excellence, Hannover Medical School
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
Falk F. R. Buettner: REBIRTH-Cluster of Excellence, Hannover Medical School
Ulrich Martin: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School
Robert Zweigerdt: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Transplantation and Vascular Surgery (HTTG), Hannover Medical School

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13602

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