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Optogenetic-Programmable Human Embryo Models Elucidate the Interplay Between Tissue Architecture and BMP4 Signaling at the Onset of Gastrulation

ABSTRACT: The spatiotemporal regulation of morphogenetic signals, along with their interaction with local tissue mechanics, guides morphogenesis and determines the shape and form of the embryo (Valet et al., 2022 PMID: 34754086; Pfeifer et al., 2024 PMID: 38181658). However, how these signals precisely integrate into developmental circuits remains poorly understood. Here, we took advantage of a light-inducible strategy (De Santis et al., 2021 PMID: 34799555) to induce BMP4 signaling with precise spatial coordinates to study epiblast symmetry breaking and its interplay with tissue mechanics at the onset of gastrulation. Light-controlled BMP4 induced SMAD1-5 phosphorylation, resulting in the differentiation of extra-embryonic amnion cells and relied on a tension-dependent induction of the WNT (Muncie et al., 2020 PMID: 33207224) and NODAL pathways for mesoderm and endoderm differentiation. In micropattern gastruloids (Warmflash et al., 2014), tissue tension signals through YAP1 (Totaro et al., 2018, PMID: 30050119). In response to BMP4 stimulation, YAP1 localizes to the nucleus where it represses WNT3 mRNA (Estras et al., 2017, PMID: 29269485), thereby regulating the induction of the three germ layers. Based on these findings, we developed a new mathematical model that integrates tissue mechanics into morphogen dynamics, quantitatively explaining cellular and tissue-scale responses to BMP4 signaling. In all, light induction of the morphogen BMP4 in human embryo models unveiled how embryonic patterning is organized in relation to specific tissue architecture and mechanics at the onset of gastrulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275856 | GEO | 2025/08/31

REPOSITORIES: GEO

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Project description:Adipose tissue is a plentiful and easily accessible source of mesenchymal stem cells that have been shown to be multi potent and possibly have immuno suppressive capacity(Zuk, Zhu et al. 2002; McIntosh, Zvonic et al. 2006; Prichard, Reichert et al. 2008). Several studies have identified hypoxia and the molecular effector of reduced oxygen tension, HIF1Î± to be essential in the differentiation processes, stem cell proliferation and survival as well as in maintenance of stem cell characteristics (Lennon, Edmison et al. 2001; Goda, Ryan et al. 2003; Wang, Fermor et al. 2005; Lin, Lee et al. 2006; Malladi, Xu et al. 2007; Ohnishi, Yasuda et al. 2007). The fact that oxygen has a central role in cell development and metabolism makes the regulation of oxygen tension a valuable tool in the attempt of exploiting stem cells to their full potential. In the current study we investigate the transcriptional changes caused by two weeks of monolayer hypoxic expansion of human adipose tissue derived stem cells (ASCs). Application of the XVivo hypoxic workstation (BioSpherix, Redfield, NY) made it possible to conduct the expansion of six ASC lines at four different hypoxic conditions in parallel covering the range from mild (15% oxygen) to full hypoxic (1% oxygen) conditions. In this comprehensive investigation the Illumina bead microarray platform was employed to give a profound and new insight in the molecular changes effectuated by hypoxic expansion. The findings of this study demonstrate the significance of biologic variation in the transcriptional response to mild hypoxic expansion and display evidence that full hypoxic growth conditions at 1% oxygen tension selects for a more prolific cell population of reduced chondrogenic potential. Keywords: hypoxia response To investigate the transcriptional response to hypoxia, adipose tissue derived stem cells (ASCs) from six female individuals were cultured for 14 days at different oxygen tensions (ambient, 15%, 10%, 5% and 1%). Gene expression levels at each oxygen tension were compared to ambient conditions (Ambient oxygen tension) using Illumina Human-6 v2.0 microarrays.

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Optogenetic-Programmable Human Embryo Models Elucidate the Interplay Between Tissue Architecture and BMP4 Signaling at the Onset of Gastrulation

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