Modelling human blastocysts by reprogramming fibroblasts into iBlastoids
Authors: Jennifer Zenker
Amander T Clark
Jan Schröder
Jose M Polo
Daniel Poppe
Xiaodong Liu
Guizhi Sun
Joseph Chen
Asma Aberkane
Ryan Lister
Yu B Y Sun
John F Ouyang
Yichen Zhou
Owen J L Rackham
Monika Mohenska
Jia Ping Tan
Sue Mei Lim
Journal: Nature (2021)
Discipline: Multidisciplinary
Keywords: Human pluripotent stem cells; trophoblast stem cells; blastocysts; early human development; in vitro
Affiliations: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia., Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, Victoria, Australia., Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia., Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore, Singapore., Australian Research Council Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, Perth, Western Australia, Australia., The Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia., Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA., Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA., Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA., Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA., Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia. ., Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, Victoria, Australia. ., Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. .

Abstract:  Human pluripotent and trophoblast stem cells have been essential alternatives to blastocysts for understanding early human development1-4. However, these simple culture systems lack the complexity to adequately model the spatiotemporal cellular and molecular dynamics that occur during early embryonic development. Here we describe the reprogramming of fibroblasts into in vitro three-dimensional models of the human blastocyst, termed iBlastoids. Characterization of iBlastoids shows that they model the overall architecture of blastocysts, presenting an inner cell mass-like structure, with epiblast- and primitive endoderm-like cells, a blastocoel-like cavity and a trophectoderm-like outer layer of cells. Single-cell transcriptomics further confirmed the presence of epiblast-, primitive endoderm-, and trophectoderm-like cells. Moreover, iBlastoids can give rise to pluripotent and trophoblast stem cells and are capable of modelling, in vitro, several aspects of the early stage of implantation. In summary, we have developed a scalable and tractable system to model human blastocyst biology; we envision that this will facilitate the study of early human development and the effects of gene mutations and toxins during early embryogenesis, as well as aiding in the development of new therapies associated with in vitro fertilization. 

Retracted: No

PubPeer comments:
 Readers should become aware of a recent preprint published on bioRxiv entitled Reprogrammed iBlastoids contain amnion-like cells but not trophectoderm , which calls into question part of the findings of Liu et al., study. https: www.biorxiv.org content 10.1101 2021.05.07.442980v1 From the abstract: Two recent papers in Nature show that human blastocyst-like structures (or blastoids) can be generated from human pluripotent stem cells (Yu et al 2021) or through reprogramming of fibroblasts (Liu et al 2021), respectively. Both papers perform extensive single cell transcriptional analysis and compare blastoid cells with the cells in preimplantation human embryos, leading to a conclusion that the blastoids contain cell lineages corresponding to the epiblast, primitive endoderm and trophectoderm in preimplantation human embryos. Transcriptional analysis is, however, critically dependent on having relevant reference samples, not only of targeted cell types but also of potential alternative cell lineages. For this reason, we have reevaluated the blastoid data with a more comprehensive cellular reference, including extended cultures of blastocysts, several stem cell-based embryo models and a gastrulation stage human specimen. **From this reanalysis we resolve that reprogrammed blastoids by Liu et al. fail to generate cells with trophectoderm profiles. Instead, cells identified as trophectoderm lineages in reprogrammed blastoids possess a transcriptional profile more representative of amniotic cells in post-implantation human embryos.** Our reanalysis also shows that stem cell-derived blastoids did contain trophectoderm-like cells, highlighting the potential of human blastoids to model blastocyst development. ,