Transient suppression of SUMOylation in embryonic stem cells generates embryo-like structures DOI Creative Commons
Jack‐Christophe Cossec, Tatiana Traboulsi, Sébastien Sart

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(4), P. 112380 - 112380

Published: April 1, 2023

Recent advances in synthetic embryology have opened new avenues for understanding the complex events controlling mammalian peri-implantation development. Here, we show that mouse embryonic stem cells (ESCs) solely exposed to chemical inhibition of SUMOylation generate embryo-like structures comprising anterior neural and trunk-associated regions. HypoSUMOylation-instructed ESCs give rise spheroids self-organize into gastrulating containing cell types spatially functionally related extraembryonic compartments. Alternatively, cultured a droplet microfluidic device form elongated undergo axial organization reminiscent natural embryo morphogenesis. Single-cell transcriptomics reveals various cellular lineages, including properly positioned neuronal paraxial mesoderm segmented somite-like structures. Transient suppression gradually increases DNA methylation genome wide repressive mark deposition at Nanog. Interestingly, cell-to-cell variations levels occur during early embryogenesis. Our approach provides proof principle potentially powerful strategies explore embryogenesis by targeting chromatin roadblocks fate change.

Language: Английский

Embryo model completes gastrulation to neurulation and organogenesis DOI Creative Commons
Gianluca Amadei, Charlotte E. Handford, Chengxiang Qiu

et al.

Nature, Journal Year: 2022, Volume and Issue: 610(7930), P. 143 - 153

Published: Aug. 25, 2022

Abstract Embryonic stem (ES) cells can undergo many aspects of mammalian embryogenesis in vitro 1–5 , but their developmental potential is substantially extended by interactions with extraembryonic cells, including trophoblast (TS) endoderm (XEN) and inducible XEN (iXEN) 6–11 . Here we assembled cell-derived embryos from mouse ES TS iXEN showed that they recapitulate the development whole natural embryo utero up to day 8.5 post-fertilization. Our model displays headfolds defined forebrain midbrain regions develops a beating heart-like structure, trunk comprising neural tube somites, tail bud containing neuromesodermal progenitors, gut tube, primordial germ cells. This complete within an yolk sac initiates blood island development. Notably, demonstrate neurulating Pax6 -knockout aggregated wild-type recapitulates ventral domain expansion occurs natural, ubiquitous embryos. Thus, these embryoids are powerful for dissecting roles diverse cell lineages genes results self-organization ability two types reconstitute through beyond gastrulation neurulation early organogenesis.

Language: Английский

Citations

192
Mouse embryo model derived exclusively from embryonic stem cells undergoes neurulation and heart development DOI Creative Commons

Kasey Y.C. Lau,

Hernan Rubinstein,

Carlos W. Gantner

et al.

Cell stem cell, Journal Year: 2022, Volume and Issue: 29(10), P. 1445 - 1458.e8

Published: Sept. 8, 2022

Several in vitro models have been developed to recapitulate mouse embryogenesis solely from embryonic stem cells (ESCs). Despite mimicking many aspects of early development, they fail capture the interactions between and extraembryonic tissues. To overcome this difficulty, we a ESC-based model that reconstitutes pluripotent ESC lineage two lineages post-implantation embryo by transcription-factor-mediated induction. This unified recapitulates developmental events day 5.5 8.5, including gastrulation; formation anterior-posterior axis, brain, beating heart structure; development tissues, yolk sac chorion. Comparing single-cell RNA sequencing individual structures with time-matched natural embryos identified remarkably similar transcriptional programs across but also showed when where diverges program. Our findings demonstrate an extraordinary plasticity ESCs self-organize generate whole-embryo-like structure.

Language: Английский

Citations

84
Dissecting peri-implantation development using cultured human embryos and embryo-like assembloids DOI Creative Commons
Zongyong Ai, Ben Niu, Yu Yin

et al.

Cell Research, Journal Year: 2023, Volume and Issue: 33(9), P. 661 - 678

Published: July 17, 2023

Studies of cultured embryos have provided insights into human peri-implantation development. However, detailed knowledge lineage development as well underlying mechanisms remains obscure. Using 3D-cultured embryos, herein we report a complete cell atlas the early post-implantation lineages and decipher cellular composition gene signatures epiblast hypoblast derivatives. In addition, develop an embryo-like assembloid (E-assembloid) by assembling naive hESCs extraembryonic cells. E-assembloids, reveal that WNT, BMP Nodal signaling pathways synergistically, but functionally differently, orchestrate Specially, dissect mesoderm endoderm specifications. Finally, improved E-assembloid is developed to recapitulate tissue architectures in pre-gastrulation embryo. Our findings provide development, offers useful model disentangle behaviors interactions drive embryogenesis.

Language: Английский

Citations

49
Multimodal characterization of murine gastruloid development DOI Creative Commons
Simon Suppinger,

Marietta Zinner,

Nadim Aizarani

et al.

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(6), P. 867 - 884.e11

Published: May 19, 2023

Gastruloids are 3D structures generated from pluripotent stem cells recapitulating fundamental principles of embryonic pattern formation. Using single-cell genomic analysis, we provide a resource mapping cell states and types during gastruloid development compare them with the in vivo embryo. We developed high-throughput handling imaging pipeline to spatially monitor symmetry breaking report an early spatial variability pluripotency determining binary response Wnt activation. Although gastruloid-core revert pluripotency, peripheral become primitive streak-like. These two populations subsequently break radial initiate axial elongation. By performing compound screen, perturbing thousands gastruloids, derive phenotypic landscape infer networks genetic interactions. Finally, using dual modulation, improve formation anterior existing model. This work provides understand how gastruloids develop generate complex patterns vitro.

Language: Английский

Citations

45
3D gastruloids: a novel frontier in stem cell-based in vitro modeling of mammalian gastrulation DOI Creative Commons
Susanne C. van den Brink, Alexander van Oudenaarden

Trends in Cell Biology, Journal Year: 2021, Volume and Issue: 31(9), P. 747 - 759

Published: July 22, 2021

3D gastruloids, aggregates of embryonic stem cells that recapitulate key aspects gastrula-stage embryos, have emerged as a powerful tool to study the early stages mammalian post-implantation development in vitro. Owing their tractable nature and relative ease by which they can be generated large numbers, gastruloids provide an unparalleled opportunity normal pathological embryogenesis from bottom-up perspective high-throughput manner. Here, we review how gastruloid models exploited deepen our understanding development. In addition, discuss current limitations, potential clinical applications, ethical implications this emerging model system.

Language: Английский

Citations

90
Gastruloids: Pluripotent stem cell models of mammalian gastrulation and embryo engineering DOI Creative Commons
Alfonso Martínez Arias, Yusuke Marikawa, Naomi Moris

et al.

Developmental Biology, Journal Year: 2022, Volume and Issue: 488, P. 35 - 46

Published: May 7, 2022

Language: Английский

Citations

44
Self-organizing models of human trunk organogenesis recapitulate spinal cord and spine co-morphogenesis DOI
Simona Gribaudo,

Rémi Robert,

Björn van Sambeek

et al.

Nature Biotechnology, Journal Year: 2023, Volume and Issue: 42(8), P. 1243 - 1253

Published: Sept. 14, 2023

Language: Английский

Citations

38
MLL3/MLL4 methyltransferase activities control early embryonic development and embryonic stem cell differentiation in a lineage-selective manner DOI
Guojia Xie, Ji‐Eun Lee, Anna D. Senft

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(4), P. 693 - 705

Published: April 1, 2023

Language: Английский

Citations

35
Harnessing synthetic biology to engineer organoids and tissues DOI Creative Commons
Coralie Trentesaux, Toshimichi Yamada, Ophir D. Klein

et al.

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(1), P. 10 - 19

Published: Jan. 1, 2023

Language: Английский

Citations

33
Optogenetic control of Wnt signaling models cell-intrinsic embryogenic patterning using 2D human pluripotent stem cell culture DOI Creative Commons
Nicole Repina, Hunter J. Johnson, Xiaoping Bao

et al.

Development, Journal Year: 2023, Volume and Issue: 150(14)

Published: July 4, 2023

ABSTRACT In embryonic stem cell (ESC) models for early development, spatially and temporally varying patterns of signaling types emerge spontaneously. However, mechanistic insight into this dynamic self-organization is limited by a lack methods spatiotemporal control signaling, the relevance signal dynamics cell-to-cell variability to pattern emergence remains unknown. Here, we combine optogenetic stimulation, imaging transcriptomic approaches study human ESCs (hESC) in two-dimensional (2D) culture. Morphogen were controlled via activation canonical Wnt/β-catenin (optoWnt), which drove broad transcriptional changes mesendoderm differentiation at high efficiency (>99% cells). When activated within subpopulations, optoWnt induced distinct epithelial mesenchymal domains, mediated migration, an mesenchymal-like transition TGFβ signaling. Furthermore, demonstrate that such subpopulations can be used uncover feedback mechanisms between neighboring types. These findings reveal Wnt sufficient generate tissue-scale patterning establish hESC model system investigating relevant embryogenesis.

Language: Английский

Citations

24