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Reprogrammed blastoids contain amnion-like cells but not trophectoderm

Cheng Zhao, Alvaro Plaza Reyes, John Paul Schell, Jere Weltner, Nicolás M. Ortega, Yi Zheng, Åsa K. Björklund, Janet Rossant, Jianping Fu, Sophie Petropoulos, Fredrik Lanner
doi: https://doi.org/10.1101/2021.05.07.442980
Cheng Zhao
1Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and Division of Obstetrics and Gynecology, Karolinska. Universitetssjukhuset, Stockholm, Sweden
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Alvaro Plaza Reyes
1Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and Division of Obstetrics and Gynecology, Karolinska. Universitetssjukhuset, Stockholm, Sweden
2Department of Regeneration and Cell Therapy, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Seville, Spain
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John Paul Schell
1Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and Division of Obstetrics and Gynecology, Karolinska. Universitetssjukhuset, Stockholm, Sweden
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Jere Weltner
1Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and Division of Obstetrics and Gynecology, Karolinska. Universitetssjukhuset, Stockholm, Sweden
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Nicolás M. Ortega
1Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and Division of Obstetrics and Gynecology, Karolinska. Universitetssjukhuset, Stockholm, Sweden
11Ming Wai Lau Center for Reparative Medicine, Stockholm Node, Karolinska Institutet, Stockholm, Sweden
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Yi Zheng
3Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
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Åsa K. Björklund
4Dept of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Husargatan 3, SE-752 37 Uppsala, Sweden
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Janet Rossant
5Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada
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Jianping Fu
3Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
6Department of Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
7Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
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Sophie Petropoulos
1Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and Division of Obstetrics and Gynecology, Karolinska. Universitetssjukhuset, Stockholm, Sweden
8Département de Médecine, Université de Montréal, Montréal Canada
9Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Axe Immunopathologie, H2X 19A Montréal, Canada
10Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, Canada
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Fredrik Lanner
1Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and Division of Obstetrics and Gynecology, Karolinska. Universitetssjukhuset, Stockholm, Sweden
11Ming Wai Lau Center for Reparative Medicine, Stockholm Node, Karolinska Institutet, Stockholm, Sweden
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  • For correspondence: fredrik.lanner@ki.se
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Abstract

With the advancement of human stem cell cultures and interest in understanding human embryogenesis, human blastocyst-like structures, or human blastoids, are being developed. Thus far, two different strategies have been taken, generating blastoids from naïve human pluripotent stem cells (hPSC)1–3 or through reprogramming of adult human somatic cells4. All these studies utilize comparative transcriptome analyses to authenticate blastoid cells and identify their counterparts in the human blastocyst5,6. However, the validity of comparative transcriptome analysis is critically hinged on including relevant reference data, not only those from targeted cell types but also from potential alternative cell lineages. Thus, we sought to reevaluate the single-cell transcriptome data from the blastoids based on a more comprehensive cellular reference, which includes data from in vitro cultured human6,7, non-human primate (NHP, Cynomolgus macaque) blastocysts8, a human stem cell-based post-implantation amniotic sac embryoid (PASE) model9, and an in vivo gastrulation-stage human embryo specimen10, using four different analysis strategies. Our analyses unequivocally support that blastoids developed by reprogramming adult human somatic cells largely fail to generate cells with a transcriptome profile consistent with the human blastocyst trophectoderm. Instead, cells identified as trophectoderm-like have a transcriptional profile more similar to the amniotic ectoderm in the gastrulating human and NHP embryos. To facilitate cell lineage identifications in human embryo models, we further identified a set of human amniotic ectoderm and trophectoderm markers that could be utilized to distinguish these two lineages. We further built a neural-network based online prediction tool, which accurately discerns the full cellular composition of blastoids.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • http://petropoulos-lanner-labs.clintec.ki.se/

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 26, 2021.
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Reprogrammed blastoids contain amnion-like cells but not trophectoderm
Cheng Zhao, Alvaro Plaza Reyes, John Paul Schell, Jere Weltner, Nicolás M. Ortega, Yi Zheng, Åsa K. Björklund, Janet Rossant, Jianping Fu, Sophie Petropoulos, Fredrik Lanner
bioRxiv 2021.05.07.442980; doi: https://doi.org/10.1101/2021.05.07.442980
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Reprogrammed blastoids contain amnion-like cells but not trophectoderm
Cheng Zhao, Alvaro Plaza Reyes, John Paul Schell, Jere Weltner, Nicolás M. Ortega, Yi Zheng, Åsa K. Björklund, Janet Rossant, Jianping Fu, Sophie Petropoulos, Fredrik Lanner
bioRxiv 2021.05.07.442980; doi: https://doi.org/10.1101/2021.05.07.442980

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