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Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):E7786-E7795. doi: 10.1073/pnas.1710470114. Epub 2017 Aug 22.

Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics.

Author information

1
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; jchtsang@cuhk.edu.hk loym@cuhk.edu.hk.
2
Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
3
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
4
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
5
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.

Abstract

The human placenta is a dynamic and heterogeneous organ critical in the establishment of the fetomaternal interface and the maintenance of gestational well-being. It is also the major source of cell-free fetal nucleic acids in the maternal circulation. Placental dysfunction contributes to significant complications, such as preeclampsia, a potentially lethal hypertensive disorder during pregnancy. Previous studies have identified significant changes in the expression profiles of preeclamptic placentas using whole-tissue analysis. Moreover, studies have shown increased levels of targeted RNA transcripts, overall and placental contributions in maternal cell-free nucleic acids during pregnancy progression and gestational complications, but it remains infeasible to noninvasively delineate placental cellular dynamics and dysfunction at the cellular level using maternal cell-free nucleic acid analysis. In this study, we addressed this issue by first dissecting the cellular heterogeneity of the human placenta and defined individual cell-type-specific gene signatures by analyzing more than 24,000 nonmarker selected cells from full-term and early preeclamptic placentas using large-scale microfluidic single-cell transcriptomic technology. Our dataset identified diverse cellular subtypes in the human placenta and enabled reconstruction of the trophoblast differentiation trajectory. Through integrative analysis with maternal plasma cell-free RNA, we resolved the longitudinal cellular dynamics of hematopoietic and placental cells in pregnancy progression. Furthermore, we were able to noninvasively uncover the cellular dysfunction of extravillous trophoblasts in early preeclamptic placentas. Our work showed the potential of integrating transcriptomic information derived from single cells into the interpretation of cell-free plasma RNA, enabling the noninvasive elucidation of cellular dynamics in complex pathological conditions.

KEYWORDS:

cell-free RNA; noninvasive prenatal testing; placenta; preeclampsia; single-cell transcriptomics

PMID:
28830992
PMCID:
PMC5604038
DOI:
10.1073/pnas.1710470114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: J.C.H.T., J.S.L.V., L.J., P.J., and Y.M.D.L. have filed patent applications based on the data generated from this work. P.J. is a consultant to Xcelom and Cirina. R.W.K.C. and Y.M.D.L. were consultants to Sequenom, Inc. R.W.K.C. and Y.M.D.L. hold equities in Sequenom and Grail. R.W.K.C. and Y.M.D.L. are founders of Xcelom and Cirina. Y.M.D.L. is a scientific cofounder of Grail.

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