Loss of TJP1 disrupts gastrulation patterning and increases differentiation toward the germ cell lineage in human pluripotent stem cells

Ivana Vasic; Ashley R G Libby; Annie Maslan; Emily A Bulger; David Zalazar; Martina Z Krakora Compagno; Aaron Streets; Kiichiro Tomoda; Shinya Yamanaka; Todd C McDevitt

doi:10.1016/j.devcel.2023.05.019

Loss of TJP1 disrupts gastrulation patterning and increases differentiation toward the germ cell lineage in human pluripotent stem cells

Dev Cell. 2023 Aug 21;58(16):1477-1488.e5. doi: 10.1016/j.devcel.2023.05.019. Epub 2023 Jun 23.

Authors

Affiliations

¹ Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA 94158, USA; UC Berkeley-UC San Francisco Graduate Program in Bioengineering, University of California, San Francisco, San Francisco, CA 94158, USA.
² Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Developmental and Stem Cell Biology Ph.D. Program, University of California, San Francisco, San Francisco, CA 94158, USA.
³ UC Berkeley-UC San Francisco Graduate Program in Bioengineering, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁴ Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
⁵ UC Berkeley-UC San Francisco Graduate Program in Bioengineering, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁶ Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Center for iPS Cell Research and Application, Kyoto 606-8397, Japan.
⁷ Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Center for iPS Cell Research and Application, Kyoto 606-8397, Japan. Electronic address: [email protected].
⁸ Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: [email protected].

Abstract

Biological patterning events that occur early in development establish proper tissue morphogenesis. Identifying the mechanisms that guide these patterning events is necessary in order to understand the molecular drivers of development and disease and to build tissues in vitro. In this study, we use an in vitro model of gastrulation to study the role of tight junctions and apical/basolateral polarity in modulating bone morphogenic protein-4 (BMP4) signaling and gastrulation-associated patterning in colonies of human pluripotent stem cells (hPSCs). Disrupting tight junctions via knockdown (KD) of the scaffolding tight junction protein-1 (TJP1, also known as ZO1) allows BMP4 to robustly and ubiquitously activate pSMAD1/5 signaling over time, resulting in loss of the patterning phenotype and marked differentiation bias of pluripotent stem cells to primordial germ cell-like cells (PGCLCs). These findings give important insights into how signaling events are regulated and lead to spatial emergence of diverse cell types in vitro.

Keywords: BMP4; PGCLCs; TJP1; cell signaling; epiblast; gastrulation; pSMAD1; tight junctions.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Cell Differentiation
Cell Lineage
Gastrulation* / physiology
Germ Cells
Humans
Pluripotent Stem Cells*
Zonula Occludens-1 Protein / genetics
Zonula Occludens-1 Protein / metabolism

Substances

TJP1 protein, human
Zonula Occludens-1 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding