Mechanistic Model-Guided Study of Embryonic Morphogenesis

Avner Ehrlich 1,2 Sabina Tsytkin-Kirschenzweig 1,2 Yoel Goldstein 1,2 Ronit Malka 1,3 Elishai Ezra Tsur 1,2 Merav Cohen 1,2 Matan Hofree 4 Daniel Kitsberg 1,2 Claudia Pienica 1 Aviv Regev 4,5 Amnon Buxboim 1,2 Yaakov Nahmias 1,2
1Grass Center for Bioengineering, Israel
2Department of Cell and Developmental Biology, Israel
3School of Engineering and Applied Sciences, USA
4Klarman Cell Observatory, USA
5Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, USA

Human development leads to the formation of mechanical microenvironments that may play a role in tissue morphogenesis. Our ability to study these physical cues is impeded by limited access to clinical samples especially during early human development. Here we utilize a finite element model of implantation mechanics to guide the in vitro micropatterning human embryonic stem cells to simulate in vivo stress gradients that form during development. Micropatterned stem cells showed early formation of GATA4+/SOX17+ primitive endoderm due to migration toward regions of high stress, while NANOG+/OCT4+ epiblast was retained in regions of low stress under spontaneous differentiation. WNT/TGFb stimulation pushed epiblast toward T+/EOMES+ transient mesendoderm that was retained in regions of low compressive stress for several days. These dynamics were abolished using a micromechanical tissue stretcher or inhibition of Myosin-II activity, suggesting that mechanical niches may direct early morphogenesis in embryonic implantation. Our work provides a unique set of tools to study the role of mechanical forces in early human development.

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