@article{4e26a702e95b475d8abe9a18be26c860,
title = "Stem-cell-derived trophoblast organoids model human placental development and susceptibility to emerging pathogens",
abstract = "Trophoblast organoids derived from placental villi provide a 3D model system of human placental development, but access to first-trimester tissues is limited. Here, we report that trophoblast stem cells isolated from naive human pluripotent stem cells (hPSCs) can efficiently self-organize into 3D stem-cell-derived trophoblast organoids (SC-TOs) with a villous architecture similar to primary trophoblast organoids. Single-cell transcriptome analysis reveals the presence of distinct cytotrophoblast and syncytiotrophoblast clusters and a small cluster of extravillous trophoblasts, which closely correspond to trophoblast identities in the post-implantation embryo. These organoid cultures display clonal X chromosome inactivation patterns previously described in the human placenta. We further demonstrate that SC-TOs exhibit selective vulnerability to emerging pathogens (SARS-CoV-2 and Zika virus), which correlates with expression levels of their respective entry factors. The generation of trophoblast organoids from naive hPSCs provides an accessible 3D model system of the developing placenta and its susceptibility to emerging pathogens.",
keywords = "SARS-CoV-2, X chromosome inactivation, Zika virus, cytotrophoblast, extravillous trophoblast, naive pluripotency, placental development, single-cell transcriptomics, syncytiotrophoblast, trophoblast organoids, trophoblast stem cells",
author = "Karvas, {Rowan M.} and Khan, {Shafqat A.} and Sonam Verma and Yan Yin and Devesha Kulkarni and Chen Dong and Park, {Kyoung mi} and Brian Chew and Eshan Sane and Fischer, {Laura A.} and Deepak Kumar and Liang Ma and Boon, {Adrianus C.M.} and Sabine Dietmann and Mysorekar, {Indira U.} and Theunissen, {Thorold W.}",
note = "Funding Information: I.U.M. serves on the Scientific Advisory Board of Luca Biologics. The Boon laboratory has received unrelated funding support in sponsored research agreements from AI Therapeutics, Green Light Biosciences Inc., and Nano targeting & Therapy BioPharma Inc. The Boon laboratory has received funding support from AbbVie Inc., for the commercial development of SARS-CoV-2 mAb. A.C.M.B. is a recipient of a licensing agreement with AbbVie Inc., for commercial development of SARS-CoV-2 mAb. Funding Information: We thank the Genome Technology Access Center at Washington University School of Medicine for assistance with scRNA-seq and the Washington University Center for Cellular Imaging and the Washington University Biology Imaging Facility for assistance with imaging. Light sheet data were generated on a Zeiss Light sheet Z.1 microscope, which was purchased with support from the Office of Research Infrastructure Programs (ORIP), a part of the NIH Office of the Director under grant OD025034. All experiments involving hESCs were approved by the Institutional Biological and Chemical Safety Committee and Embryonic Stem Cell Research Oversight Committee at Washington University School of Medicine. We thank Angela Bowman and Lilianna Solnica-Krezel for critical reading of the manuscript. This work was supported by the National Institutes of Health (NIH) Director's New Innovator Award (DP2 GM137418) and grants from the Children's Discovery Institute (CDI-LI-2019-819), the Shipley Foundation Program for Innovation in Stem Cell Science, and the Edward Mallinckrodt, Jr. Foundation to T.W.T. R.M.K. is supported by a Training in Regenerative Medicine training grant (T32 EB028092) from the NIH. I.U.M. is supported by NIH/NICHD grant R01 HD091218 and 3R01HD091218-04S1 (RADx-UP Supplement) and a McDonnell International Academy Award. L.M. is supported by NIH grant R01 HD106120. Federal NIH/NIGMS funds were not used to develop integrated 3D models of human embryonic development. R.M.K. established and characterized SC-TO cultures under supervision of T.W.T. R.M.K. S.V. and D. Kumar performed SARS-CoV-2 pseudovirus and ZIKV infections under supervision of I.U.M. A.C.M.B. performed infections with live SARS-CoV-2 virus. K.P. B.C. E.S. and L.A.F. assisted R.M.K. with tissue culture and molecular biology experiments. C.D. derived hTSCs from naive hPSCs. S.A.K. studied XCI dynamics using the bi-allelic reporter system. Y.Y. and L.M. helped establish co-culture assays with human endometrial cells. D. Kulkarni analyzed scRNA-seq data under supervision of S.D. R.M.K. and T.W.T. analyzed and interpreted the results and wrote the paper with input from S.D. I.U.M. and A.C.M.B. I.U.M. serves on the Scientific Advisory Board of Luca Biologics. The Boon laboratory has received unrelated funding support in sponsored research agreements from AI Therapeutics, Green Light Biosciences Inc. and Nano targeting & Therapy BioPharma Inc. The Boon laboratory has received funding support from AbbVie Inc. for the commercial development of SARS-CoV-2 mAb. A.C.M.B. is a recipient of a licensing agreement with AbbVie Inc. for commercial development of SARS-CoV-2 mAb. Funding Information: We thank the Genome Technology Access Center at Washington University School of Medicine for assistance with scRNA-seq and the Washington University Center for Cellular Imaging and the Washington University Biology Imaging Facility for assistance with imaging. Light sheet data were generated on a Zeiss Light sheet Z.1 microscope, which was purchased with support from the Office of Research Infrastructure Programs (ORIP), a part of the NIH Office of the Director under grant OD025034. All experiments involving hESCs were approved by the Institutional Biological and Chemical Safety Committee and Embryonic Stem Cell Research Oversight Committee at Washington University School of Medicine. We thank Angela Bowman and Lilianna Solnica-Krezel for critical reading of the manuscript. This work was supported by the National Institutes of Health ( NIH ) Director's New Innovator Award ( DP2 GM137418 ) and grants from the Children{\textquoteright}s Discovery Institute ( CDI-LI-2019-819 ), the Shipley Foundation Program for Innovation in Stem Cell Science , and the Edward Mallinckrodt , Jr. Foundation to T.W.T. R.M.K. is supported by a Training in Regenerative Medicine training grant ( T32 EB028092 ) from the NIH. I.U.M. is supported by NIH/ NICHD grant R01 HD091218 and 3R01HD091218-04S1 (RADx-UP Supplement) and a McDonnell International Academy Award . L.M. is supported by NIH grant R01 HD106120 . Federal NIH/ NIGMS funds were not used to develop integrated 3D models of human embryonic development. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = may,
day = "5",
doi = "10.1016/j.stem.2022.04.004",
language = "English",
volume = "29",
pages = "810--825.e8",
journal = "Cell Stem Cell",
issn = "1934-5909",
number = "5",
}