Spatial multiomic landscape of the human placenta at molecular resolution

Johain R Ounadjela; Ke Zhang; Koseki J Kobayashi-Kirschvink; Kang Jin; Andrew J C Russell; Andreas I Lackner; Claire Callahan; Francesca Viggiani; Kushal K Dey; Karthik Jagadeesh; Theresa Maxian; Anna-Maria Prandstetter; Naeem Nadaf; Qiyu Gong; Ruth Raichur; Morgan L Zvezdov; Mingyang Hui; Mattew Simpson; Xinwen Liu; Wei Min; Martin Knöfler; Fei Chen; Sandra Haider; Jian Shu

doi:10.1038/s41591-024-03073-9

Spatial multiomic landscape of the human placenta at molecular resolution

Nat Med. 2024 Nov 20. doi: 10.1038/s41591-024-03073-9. Online ahead of print.

Authors

Johain R Ounadjela^#^{1

2

3}, Ke Zhang^#¹, Koseki J Kobayashi-Kirschvink^#^{2

4}, Kang Jin^#^{1

5

6}, Andrew J C Russell^#^{2

7}, Andreas I Lackner^#⁸, Claire Callahan¹, Francesca Viggiani¹, Kushal K Dey^{9

10}, Karthik Jagadeesh², Theresa Maxian¹¹, Anna-Maria Prandstetter¹¹, Naeem Nadaf², Qiyu Gong², Ruth Raichur², Morgan L Zvezdov^{1

12}, Mingyang Hui¹, Mattew Simpson¹, Xinwen Liu¹³, Wei Min^{13

14}, Martin Knöfler¹¹, Fei Chen^{15

16}, Sandra Haider¹⁷, Jian Shu^{18

19}

Affiliations

¹ Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
² Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ New York University Grossman School of Medicine, New York, NY, USA.
⁴ Laser Biomedical Research Center, G. R. Harrison Spectroscopy Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁶ Department of Biomedical Informatics, University of Cincinnati, Cincinnati, OH, USA.
⁷ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
⁸ Maternal-Fetal Immunology Group, Reproductive Biology Unit, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
⁹ Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰ Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Weill Cornell Medicine, New York, NY, USA.
¹¹ Placental Development Group, Reproductive Biology Unit, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
¹² Department of Genetics and Development, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
¹³ Department of Chemistry, Columbia University, New York, NY, USA.
¹⁴ Kavli Institute for Brain Science, Columbia University, New York, NY, USA.
¹⁵ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. chenf@broadinstitute.org.
¹⁶ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. chenf@broadinstitute.org.
¹⁷ Placental Development Group, Reproductive Biology Unit, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria. sandra.haider@muv.ac.at.
¹⁸ Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. jian.shu@mgh.harvard.edu.
¹⁹ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. jian.shu@mgh.harvard.edu.

^# Contributed equally.

PMID: 39567716
DOI: 10.1038/s41591-024-03073-9

Abstract

Successful pregnancy relies directly on the placenta's complex, dynamic, gene-regulatory networks. Disruption of this vast collection of intercellular and intracellular programs leads to pregnancy complications and developmental defects. In the present study, we generated a comprehensive, spatially resolved, multimodal cell census elucidating the molecular architecture of the first trimester human placenta. We utilized paired single-nucleus (sn)ATAC (assay for transposase accessible chromatin) sequencing and RNA sequencing (RNA-seq), spatial snATAC-seq and RNA-seq, and in situ sequencing and hybridization mapping of transcriptomes at molecular resolution to spatially reconstruct the joint epigenomic and transcriptomic regulatory landscape. Paired analyses unraveled intricate tumor-like gene expression and transcription factor motif programs potentially sustaining the placenta in a hostile uterine environment; further investigation of gene-linked cis-regulatory elements revealed heightened regulatory complexity that may govern trophoblast differentiation and placental disease risk. Complementary spatial mapping techniques decoded these programs within the placental villous core and extravillous trophoblast cell column architecture while simultaneously revealing niche-establishing transcriptional elements and cell-cell communication. Finally, we computationally imputed genome-wide, multiomic single-cell profiles and spatially characterized the placental chromatin accessibility landscape. This spatially resolved, single-cell multiomic framework of the first trimester human placenta serves as a blueprint for future studies on early placental development and pregnancy.