Synthetic organizer cells guide development via spatial and biochemical instructions

Toshimichi Yamada; Coralie Trentesaux; Jonathan M Brunger; Yini Xiao; Adam J Stevens; Iain Martyn; Petr Kasparek; Neha P Shroff; Angelica Aguilar; Benoit G Bruneau; Dario Boffelli; Ophir D Klein; Wendell A Lim

doi:10.1016/j.cell.2024.11.017

Synthetic organizer cells guide development via spatial and biochemical instructions

Cell. 2024 Dec 11:S0092-8674(24)01323-0. doi: 10.1016/j.cell.2024.11.017. Online ahead of print.

Affiliations

¹ Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
² Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Gladstone Institutes, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA 90048, USA.
⁵ Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA 90048, USA. Electronic address: ophir.klein@cshs.org.
⁶ Cell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: wendell.lim@ucsf.edu.

PMID: 39706189
DOI: 10.1016/j.cell.2024.11.017

Abstract

In vitro development relies primarily on treating progenitor cells with media-borne morphogens and thus lacks native-like spatial information. Here, we engineer morphogen-secreting organizer cells programmed to self-assemble, via cell adhesion, around mouse embryonic stem (ES) cells in defined architectures. By inducing the morphogen WNT3A and its antagonist DKK1 from organizer cells, we generated diverse morphogen gradients, varying in range and steepness. These gradients were strongly correlated with morphogenetic outcomes: the range of minimum-maximum WNT activity determined the resulting range of anterior-to-posterior (A-P) axis cell lineages. Strikingly, shallow WNT activity gradients, despite showing truncated A-P lineages, yielded higher-resolution tissue morphologies, such as a beating, chambered cardiac-like structure associated with an endothelial network. Thus, synthetic organizer cells, which integrate spatial, temporal, and biochemical information, provide a powerful way to systematically and flexibly direct the development of ES or other progenitor cells in different directions within the morphogenetic landscape.

Keywords: developmental biology; differential adhesion; gastruloid; morphogen gradient; regenerative medicine; signaling center; synCAMs; synthetic biology; synthetic cell adhesion molecules; synthetic embryos; synthetic organizer.