[ { "id": "authors:v27bb-hhe02", "collection": "authors", "collection_id": "v27bb-hhe02", "cite_using_url": "https://authors.library.caltech.edu/records/v27bb-hhe02", "type": "article", "title": "Efficient stem cell-derived mouse embryo models for environmental studies", "author": [ { "family_name": "Jorgensen", "given_name": "Victoria", "orcid": "0000-0002-4205-6198", "clpid": "Jorgensen-Victoria-Lynn" }, { "family_name": "Bao", "given_name": "Min", "orcid": "0009-0002-4247-3511", "clpid": "Bao-Min" }, { "family_name": "Junyent", "given_name": "Sergi", "orcid": "0000-0003-2405-5885", "clpid": "Junyent-Sergi" }, { "family_name": "H\u00e4felfinger", "given_name": "Christoph M.", "orcid": "0009-0000-2800-9144", "clpid": "H\u00e4felfinger-Christoph-M" }, { "family_name": "Amaya", "given_name": "Laura", "orcid": "0000-0002-8742-9111", "clpid": "Amaya-Laura" }, { "family_name": "Liao", "given_name": "Zhaodi", "orcid": "0000-0002-5387-732X", "clpid": "Liao-Zhaodi" }, { "family_name": "Williams", "given_name": "Brian A.", "orcid": "0000-0003-3253-611X", "clpid": "Williams-Brian-A" }, { "family_name": "Chen", "given_name": "Dong-Yuan", "orcid": "0000-0003-2179-2847", "clpid": "Chen-Dong-Yuan" }, { "family_name": "Wu", "given_name": "Amanda", "orcid": "0000-0001-9546-1472" }, { "family_name": "Thomson", "given_name": "Matt", "orcid": "0000-0003-1021-1234", "clpid": "Thomson-M-W" }, { "family_name": "Zernicka-Goetz", "given_name": "Magdalena", "orcid": "0000-0002-7004-2471", "clpid": "Zernicka-Goetz-M" } ], "abstract": "Blastoids are stem cell-derived structures that mimic natural blastocysts by incorporating all three lineages: trophectoderm, epiblast, and primitive endoderm. However, current methods often yield incomplete structures that fail to cavitate or to form a proper primitive endoderm. To overcome these limitations, we develop a modular approach by aggregating three murine stem cell types: embryonic stem cells (ESCs), ESCs with inducible GATA4 expression (iG4-ESCs), and trophoblast stem cells (TSCs). This method yields cavitated blastocyst-like structures-termed iG4-blastoids-with approximately 80% efficiency. Single-cell RNA sequencing confirms their close resemblance to mature mouse blastocysts. Notably, culturing iG4-blastoids without FGF4 enhances specification of the invasive mural trophectoderm, and approximately 12% of structures undergo post-implantation-like morphogenesis in vitro. Using this model, we show that caffeine, alcohol, nicotine, and amino acid variations affect iG4-blastoids and natural embryos similarly, underscoring their utility as a robust model for investigating the impact of diverse environmental factors on embryogenesis.", "doi": "10.1016/j.devcel.2025.08.004", "issn": "1534-5807", "publisher": "Elsevier", "publication": "Developmental Cell", "publication_date": "2026-01-14", "series_number": "1", "volume": "61", "issue": "1", "pages": "193-207.e6" }, { "id": "authors:wgy1x-2tf47", "collection": "authors", "collection_id": "wgy1x-2tf47", "cite_using_url": "https://authors.library.caltech.edu/records/wgy1x-2tf47", "type": "article", "title": "Temporal BMP4 effects on mouse embryonic and extraembryonic development", "author": [ { "family_name": "Hadas", "given_name": "Ron" }, { "family_name": "Rubinstein", "given_name": "Hernan" }, { "family_name": "Mittnenzweig", "given_name": "Markus" }, { "family_name": "Mayshar", "given_name": "Yoav" }, { "family_name": "Ben-Yair", "given_name": "Raz" }, { "family_name": "Cheng", "given_name": "Saifeng" }, { "family_name": "Aguilera-Castrejon", "given_name": "Alejandro", "orcid": "0000-0002-1339-7778" }, { "family_name": "Reines", "given_name": "Netta" }, { "family_name": "Orenbuch", "given_name": "Ayelet-Hashahar" }, { "family_name": "Lifshitz", "given_name": "Aviezer", "orcid": "0000-0002-8458-9507" }, { "family_name": "Chen", "given_name": "Dong-Yuan", "orcid": "0000-0003-2179-2847", "clpid": "Chen-Dong-Yuan" }, { "family_name": "Elowitz", "given_name": "Michael B.", "orcid": "0000-0002-1221-0967", "clpid": "Elowitz-M-B" }, { "family_name": "Zernicka-Goetz", "given_name": "Magdalena", "orcid": "0000-0002-7004-2471", "clpid": "Zernicka-Goetz-M" }, { "family_name": "Hanna", "given_name": "Jacob H.", "orcid": "0000-0003-2042-9974" }, { "family_name": "Tanay", "given_name": "Amos", "orcid": "0000-0001-9419-3824" }, { "family_name": "Stelzer", "given_name": "Yonatan", "orcid": "0000-0001-9207-1479" } ], "abstract": "

The developing placenta, which in mice originates through the extraembryonic ectoderm (ExE), is essential for mammalian embryonic development. Yet unbiased characterization of the differentiation dynamics of the ExE and its interactions with the embryo proper remains incomplete. Here we develop a temporal single-cell model of mouse gastrulation that maps continuous and parallel differentiation in embryonic and extraembryonic lineages. This is matched with a three-way perturbation approach to target signalling from the embryo proper, the ExE alone, or both. We show that ExE specification involves early spatial and transcriptional bifurcation of uncommitted ectoplacental cone cells and chorion progenitors. Early BMP4 signalling from chorion progenitors is required for proper differentiation of uncommitted ectoplacental cone cells and later for their specification towards trophoblast giant cells. We also find biphasic regulation by BMP4 in the embryo. The early ExE-originating BMP4 signal is necessary for proper mesoendoderm bifurcation and for allantois and primordial germ cell specification. However, commencing at embryonic day 7.5, embryo-derived BMP4 restricts the primordial germ cell pool size by favouring differentiation of their extraembryonic mesoderm precursors towards an allantois fate. ExE and embryonic tissues are therefore entangled in time, space and signalling axes, highlighting the importance of their integrated understanding and modelling in vivo and in vitro.

", "doi": "10.1038/s41586-024-07937-5", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "2024-10-17", "volume": "634", "pages": "652\u2013661" }, { "id": "authors:wn4wr-xfb87", "collection": "authors", "collection_id": "wn4wr-xfb87", "cite_using_url": "https://authors.library.caltech.edu/records/wn4wr-xfb87", "type": "article", "title": "The first two blastomeres contribute unequally to the human embryo", "author": [ { "family_name": "Junyent", "given_name": "Sergi", "orcid": "0000-0003-2405-5885", "clpid": "Junyent-Sergi" }, { "family_name": "Meglicki", "given_name": "Maciej", "orcid": "0009-0000-9224-3795", "clpid": "Meglicki-Maciej" }, { "family_name": "Vetter", "given_name": "Roman", "orcid": "0000-0003-2901-7036", "clpid": "Vetter-Roman" }, { "family_name": "Mandelbaum", "given_name": "Rachel" }, { "family_name": "King", "given_name": "Catherine", "orcid": "0009-0004-8477-1212", "clpid": "King-Catherine" }, { "family_name": "Patel", "given_name": "Ekta M.", "clpid": "Patel-Ekta-M" }, { "family_name": "Iwamoto-Stohl", "given_name": "Lisa", "orcid": "0000-0003-0776-054X", "clpid": "Iwamoto-Stohl-Lisa" }, { "family_name": "Reynell", "given_name": "Clare", "orcid": "0000-0003-2733-3334", "clpid": "Reynell-Clare" }, { "family_name": "Chen", "given_name": "Dong-Yuan", "orcid": "0000-0003-2179-2847", "clpid": "Chen-Dong-Yuan" }, { "family_name": "Rubino", "given_name": "Patrizia", "orcid": "0000-0002-1701-3946", "clpid": "Rubino-Patrizia" }, { "family_name": "Arrach", "given_name": "Nabil", "orcid": "0000-0002-0803-9626", "clpid": "Arrach-Nabil" }, { "family_name": "Paulson", "given_name": "Richard J.", "clpid": "Paulson-Richard-J" }, { "family_name": "Iber", "given_name": "Dagmar" }, { "family_name": "Zernicka-Goetz", "given_name": "Magdalena", "orcid": "0000-0002-7004-2471", "clpid": "Zernicka-Goetz-M" } ], "abstract": "
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Retrospective lineage reconstruction of humans predicts that dramatic clonal imbalances in the body can be traced to the 2-cell stage embryo. However, whether and how such clonal asymmetries arise in the embryo is unclear. Here, we performed prospective lineage tracing of human embryos using live imaging, non-invasive cell labeling, and computational predictions to determine the contribution of each 2-cell stage blastomere to the epiblast (body), hypoblast (yolk sac), and trophectoderm (placenta). We show that the majority of epiblast cells originate from only one blastomere of the 2-cell stage embryo. We observe that only one to three cells become internalized at the 8-to-16-cell stage transition. Moreover, these internalized cells are more frequently derived from the first cell to divide at the 2-cell stage. We propose that cell division dynamics and a cell internalization bottleneck in the early embryo establish asymmetry in the clonal composition of the future human body.

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", "doi": "10.1016/j.cell.2024.04.029", "issn": "0092-8674", "publisher": "Cell Press", "publication": "Cell", "publication_date": "2024-05-23", "series_number": "11", "volume": "187", "issue": "11", "pages": "2838-2854.e17" }, { "id": "authors:5bqk7-b1e47", "collection": "authors", "collection_id": "5bqk7-b1e47", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20230602-251540000.11", "type": "article", "title": "Stem cell-derived synthetic embryos self-assemble by exploiting cadherin codes and cortical tension", "author": [ { "family_name": "Bao", "given_name": "Min", "orcid": "0000-0003-0992-9388", "clpid": "Bao-Min" }, { "family_name": "Cornwall-Scoones", "given_name": "Jake", "orcid": "0000-0002-7435-486X", "clpid": "Cornwall-Scoones-Jake" }, { "family_name": "Sanchez-Vasquez", "given_name": "Estefania", "orcid": "0000-0002-6585-8548", "clpid": "Sanchez-Vasquez-Estefania" }, { "family_name": "Cox", "given_name": "Andy L.", "clpid": "Cox-Andy-L" }, { "family_name": "Chen", "given_name": "Dong-Yuan", "orcid": "0000-0003-2179-2847", "clpid": "Chen-Dong-Yuan" }, { "family_name": "De Jonghe", "given_name": "Joachim", "orcid": "0000-0003-0584-8265", "clpid": "De-Jonghe-Joachim" }, { "family_name": "Shadkhoo", "given_name": "Shahriar", "orcid": "0000-0003-3582-0634", "clpid": "Shadkhoo-Shahriar" }, { "family_name": "Hollfelder", "given_name": "Florian", "orcid": "0000-0002-1367-6312", "clpid": "Hollfelder-Florian" }, { "family_name": "Thomson", "given_name": "Matt", "orcid": "0000-0003-1021-1234", "clpid": "Thomson-M-W" }, { "family_name": "Glover", "given_name": "David M.", "orcid": "0000-0003-0956-0103", "clpid": "Glover-D-M" }, { "family_name": "Zernicka-Goetz", "given_name": "Magdalena", "orcid": "0000-0002-7004-2471", "clpid": "Zernicka-Goetz-M" } ], "abstract": "Mammalian embryos sequentially differentiate into trophectoderm and an inner cell mass, the latter of which differentiates into primitive endoderm and epiblast. Trophoblast stem (TS), extraembryonic endoderm (XEN) and embryonic stem (ES) cells derived from these three lineages can self-assemble into synthetic embryos, but the mechanisms remain unknown. Here, we show that a stem cell-specific cadherin code drives synthetic embryogenesis. The XEN cell cadherin code enables XEN cell sorting into a layer below ES cells, recapitulating the sorting of epiblast and primitive endoderm before implantation. The TS cell cadherin code enables TS cell sorting above ES cells, resembling extraembryonic ectoderm clustering above epiblast following implantation. Whereas differential cadherin expression drives initial cell sorting, cortical tension consolidates tissue organization. By optimizing cadherin code expression in different stem cell lines, we tripled the frequency of correctly formed synthetic embryos. Thus, by exploiting cadherin codes from different stages of development, lineage-specific stem cells bypass the preimplantation structure to directly assemble a postimplantation embryo.", "doi": "10.1038/s41556-022-00984-y", "pmcid": "PMC9481465", "issn": "1465-7392", "publisher": "Nature Publishing Group", "publication": "Nature Cell Biology", "publication_date": "2023-09", "series_number": "9", "volume": "24", "issue": "9", "pages": "1341-2349" }, { "id": "authors:ny5rx-x3886", "collection": "authors", "collection_id": "ny5rx-x3886", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20221010-454096500.25", "type": "article", "title": "Embryo\u00a0model completes gastrulation to neurulation and organogenesis", "author": [ { "family_name": "Amadei", "given_name": "Gianluca", "orcid": "0000-0001-5405-968X", "clpid": "Amadei-Gianluca" }, { "family_name": "Handford", "given_name": "Charlotte E.", "orcid": "0000-0002-5245-8027", "clpid": "Handford-Charlotte-E" }, { "family_name": "Qiu", "given_name": "Chengxiang", "orcid": "0000-0002-6346-8669", "clpid": "Qiu-Chengxiang" }, { "family_name": "De Jonghe", "given_name": "Joachim", "orcid": "0000-0003-0584-8265", "clpid": "De-Jonghe-Joachim" }, { "family_name": "Greenfeld", "given_name": "Hannah", "clpid": "Greenfeld-Hannah" }, { "family_name": "Tran", "given_name": "Martin", "clpid": "Tran-Martin" }, { "family_name": "Martin", "given_name": "Beth K.", "orcid": "0000-0002-9661-014X", "clpid": "Martin-Beth-K" }, { "family_name": "Chen", "given_name": "Dong-Yuan", "orcid": "0000-0003-2179-2847", "clpid": "Chen-Dong-Yuan" }, { "family_name": "Aguilera-Castrejon", "given_name": "Alejandro", "orcid": "0000-0002-1339-7778", "clpid": "Aguilera-Castrejon-Alejandro" }, { "family_name": "Hanna", "given_name": "Jacob H.", "orcid": "0000-0003-2042-9974", "clpid": "Hanna-Jacob-H" }, { "family_name": "Elowitz", "given_name": "Michael B.", "orcid": "0000-0002-1221-0967", "clpid": "Elowitz-M-B" }, { "family_name": "Hollfelder", "given_name": "Florian", "orcid": "0000-0002-1367-6312", "clpid": "Hollfelder-Florian" }, { "family_name": "Shendure", "given_name": "Jay", "orcid": "0000-0002-1516-1865", "clpid": "Shendure-Jay" }, { "family_name": "Glover", "given_name": "David M.", "orcid": "0000-0003-0956-0103", "clpid": "Glover-D-M" }, { "family_name": "Zernicka-Goetz", "given_name": "Magdalena", "orcid": "0000-0002-7004-2471", "clpid": "Zernicka-Goetz-M" } ], "abstract": "Embryonic stem (ES) cells can undergo many aspects of mammalian embryogenesis in vitro, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem (TS) cells, extraembryonic endoderm stem (XEN) cells and inducible XEN (iXEN) cells. Here we assembled stem cell-derived embryos in vitro from mouse ES cells, TS cells and iXEN cells and showed that they recapitulate the development of whole natural mouse embryo in utero up to day 8.5 post-fertilization. Our embryo model displays headfolds with defined forebrain and midbrain regions and develops a beating heart-like structure, a trunk comprising a neural tube and somites, a tail bud containing neuromesodermal progenitors, a gut tube, and primordial germ cells. This complete embryo model develops within an extraembryonic yolk sac that initiates blood island development. Notably, we demonstrate that the neurulating embryo model assembled from Pax6-knockout ES cells aggregated with wild-type TS cells and iXEN cells recapitulates the ventral domain expansion of the neural tube that occurs in natural, ubiquitous Pax6-knockout embryos. Thus, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse cell lineages and genes in development. Our results demonstrate the self-organization ability of ES cells and two types of extraembryonic stem cells to reconstitute mammalian development through and beyond gastrulation to neurulation and early organogenesis.", "doi": "10.1038/s41586-022-05246-3", "pmcid": "PMC9534772", "issn": "0028-0836", "publisher": "Nature Publishing Group", "publication": "Nature", "publication_date": "2022-10-06", "series_number": "7930", "volume": "610", "issue": "7930", "pages": "143-153" }, { "id": "authors:am7bp-3g465", "collection": "authors", "collection_id": "am7bp-3g465", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220919-149101800", "type": "article", "title": "Stem cell-derived synthetic embryos self-assemble by exploiting cadherin codes and cortical tension", "author": [ { "family_name": "Bao", "given_name": "Min", "orcid": "0000-0003-0992-9388", "clpid": "Bao-Min" }, { "family_name": "Cornwall-Scoones", "given_name": "Jake", "orcid": "0000-0002-7435-486X", "clpid": "Cornwall-Scoones-Jake" }, { "family_name": "Sanchez-Vasquez", "given_name": "Estefania", "orcid": "0000-0002-6585-8548", "clpid": "Sanchez-Vasquez-Estefania" }, { "family_name": "Cox", "given_name": "Andy L.", "clpid": "Cox-Andy-L" }, { "family_name": "Chen", "given_name": "Dong-Yuan", "orcid": "0000-0003-2179-2847", "clpid": "Chen-Dong-Yuan" }, { "family_name": "De Jonghe", "given_name": "Joachim", "orcid": "0000-0003-0584-8265", "clpid": "De-Jonghe-Joachim" }, { "family_name": "Shadkhoo", "given_name": "Shahriar", "orcid": "0000-0003-3582-0634", "clpid": "Shadkhoo-Shahriar" }, { "family_name": "Hollfelder", "given_name": "Florian", "orcid": "0000-0002-1367-6312", "clpid": "Hollfelder-Florian" }, { "family_name": "Thomson", "given_name": "Matt", "orcid": "0000-0003-1021-1234", "clpid": "Thomson-M-W" }, { "family_name": "Glover", "given_name": "David M.", "orcid": "0000-0003-0956-0103", "clpid": "Glover-D-M" }, { "family_name": "Zernicka-Goetz", "given_name": "Magdalena", "orcid": "0000-0002-7004-2471", "clpid": "Zernicka-Goetz-M" } ], "abstract": "Mammalian embryos sequentially differentiate into trophectoderm and an inner cell mass, the latter of which differentiates into primitive endoderm and epiblast. Trophoblast stem (TS), extraembryonic endoderm (XEN) and embryonic stem (ES) cells derived from these three lineages can self-assemble into synthetic embryos, but the mechanisms remain unknown. Here, we show that a stem cell-specific cadherin code drives synthetic embryogenesis. The XEN cell cadherin code enables XEN cell sorting into a layer below ES cells, recapitulating the sorting of epiblast and primitive endoderm before implantation. The TS cell cadherin code enables TS cell sorting above ES cells, resembling extraembryonic ectoderm clustering above epiblast following implantation. Whereas differential cadherin expression drives initial cell sorting, cortical tension consolidates tissue organization. By optimizing cadherin code expression in different stem cell lines, we tripled the frequency of correctly formed synthetic embryos. Thus, by exploiting cadherin codes from different stages of development, lineage-specific stem cells bypass the preimplantation structure to directly assemble a postimplantation embryo.", "doi": "10.1038/s41556-022-00984-y", "pmcid": "PMC9481465", "issn": "1465-7392", "publisher": "Nature Publishing Group", "publication": "Nature Cell Biology", "publication_date": "2022-09-13", "series_number": "9", "volume": "24", "issue": "9", "pages": "1341-1349" } ]