Modelling Human Post-Implantation Development via Extra-Embryonic Niche Engineering

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Implantation of the human embryo commences a critical developmental stage that comprises profound morphogenetic alteration of embryonic and extra-embryonic tissues, axis formation, and gastrulation events. Our mechanistic knowledge of this window of human life remains limited due to restricted access to in vivo samples for both technical and ethical reasons. Additionally, human stem cell models of early post-implantation development with both embryonic and extra-embryonic tissue morphogenesis are lacking. Here, we present iDiscoid, produced from human induced pluripotent stem cells via an engineered a synthetic gene circuit. iDiscoids exhibit reciprocal co-development of human embryonic tissue and engineered extra-embryonic niche in a model of human post-implantation. They exhibit unanticipated self-organization and tissue boundary formation that recapitulates yolk sac-like tissue specification with extra-embryonic mesoderm and hematopoietic characteristics, the formation of bilaminar disc-like embryonic morphology, the development of an amniotic-like cavity, and acquisition of an anterior-like hypoblast pole and posterior-like axis. iDiscoids offer an easy-to-use, high-throughput, reproducible, and scalable platform to probe multifaceted aspects of human early post-implantation development. Thus, they have the potential to provide a tractable human model for drug testing, developmental toxicology, and disease modeling.

Authors 17

1. Joshua Hislop

   University of Pittsburgh

   Affiliation as printed

   Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA

   Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

   Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA

2. Amir Alavi

   Carnegie Mellon University

   Affiliation as printed

   Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA

   Machine Learning Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA

3. Qi Song

   Carnegie Mellon University

   Affiliation as printed

   Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA

   Machine Learning Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA

4. Rayna Schoenberger

   University of Pittsburgh

   Affiliation as printed

   Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA

   Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA

5. Kamyar Keshavarz F.

   University of Pittsburgh

   Affiliation as printed

   Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA

   Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

   Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA

6. Ryan LeGraw

   University of Pittsburgh

   Affiliation as printed

   Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

   Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA

7. Jeremy J. Velazquez

   University of Pittsburgh

   Affiliation as printed

   Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

   Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA

8. Tahere Mokhtari

   University of Pittsburgh

   Affiliation as printed

   Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA

   Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

   Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA

9. Mohammad Nasser Taheri

   University of Pittsburgh

   Affiliation as printed

   Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA

   Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

   Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA

10. Matthew Rytel

    University of Pittsburgh

    Affiliation as printed

    Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

    Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA

11. Susana M. Chuva de Sousa Lopes Aachen Department of Anatomy and Embryology

    Leiden University Medical Center

    Affiliation as printed

    Department of Anatomy and Embryology, Leiden University Medical Center, Einthovenweg, 2333 ZC Leiden, the Netherlands

12. Simon C. Watkins

    University of Pittsburgh

    Affiliation as printed

    Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA

    Department of Cell Biology and Molecular Physiology, University of Pittsburgh, Pittsburgh, PA, USA

13. Donna Beer Stolz

    University of Pittsburgh

    Affiliation as printed

    Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA

    Department of Cell Biology and Molecular Physiology, University of Pittsburgh, Pittsburgh, PA, USA

14. Samira Kiani

    University of Pittsburgh · McGowan Institute for Regenerative Medicine

    Affiliation as printed

    Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA

    Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA

    Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA

    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 1521, USA

15. Berna Sözen

    Yale University

    Affiliation as printed

    Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, 06510, USA

    Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, 065, USA

16. Ziv Bar‐Joseph

    Carnegie Mellon University

    Affiliation as printed

    Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA

    Machine Learning Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA

17. Mo R. Ebrahimkhani corresponding

    University of Pittsburgh · McGowan Institute for Regenerative Medicine

    Affiliation as printed

    Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA

    Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA

    Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA

    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 1521, USA