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  1. Evaluation Summary:

    By using single-cell RNA sequencing, elegant computational approaches, protein validation, and in vitro functional assays, this study characterizes the cellular composition and gene expression profiles of the human placenta in mid-gestation. The findings and dataset provided by the authors represent an important resource for readers interested in human development and placenta biology. However, conclusions require additional experimental support.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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  2. Reviewer #1 (Public Review):

    The authors use single-cell RNA-sequencing to identify cell types and molecular mechanisms between two distinct regions in the second-trimester human placenta: the villous chorion and the smooth chorion. Two major descriptions are of important interest. Based on their elegant transcriptomic analysis, the authors identify a new subset of cytotrophoblasts (CTBs) which they termed smooth-chorion-specific CTB (SC-CTBs). Based on the transcriptomic profile, the authors suggest that the role of the SC-CTBs is in form of an epidermal-like barrier and blockage of aberrant syncytiotrophoblast (STBs) differentiation. Moreover, the authors show a close association of SC-CTBs with extravillous trophoblasts (EVTs) and they suggest that SC-CTBs secrete factors that inhibit EVT migration.

    I find that the study tries to answer a novel question in the field. Their results could be of interest to the community in the field.

    They are some additional aspects the authors could address.

    - In the method section, I would suggest the authors explain in detail how the cellular isolations of VC and SC trophoblasts were performed and not just cite other papers. In addition, it would be good to know how the samples were obtained. Were they normal pregnancies?
    - Would it be possible for the authors to validate their data to re-analyze other publicly available datasets on the first and third-trimester placenta. Do they find similar findings for EVTs? It would be extremely interesting if they could infer how EVTs change throughout gestation.
    - The findings on SC-CTB-secreted factors inhibiting EVT invasion are very intriguing. Could the authors analyze the conditioned media (via mass spec or ELISA) from SC and VC to try to identify potential candidates (e.g. SERPINE1 as mentioned in the discussion)?

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  3. Reviewer #2 (Public Review):

    In this study, the authors utilized single-cell RNA-sequencing (scRNA-seq) to characterize the cellular composition and gene expression profiles between the villous and smooth chorion of the human placenta in mid-gestation. The authors first identified major cell clusters, including cytotrophoblast (CTB), extravillous trophoblast (EVT), stromal cells, epithelial cells, and immune cells. Based on trajectory analyses, the authors show that CTB in the villous chorion differentiate into syncytiotrophoblast (STB), whereas those in the smooth chorion produced a newly classified CTB subset termed smooth-chorion-specific CTB (SC-CTB). Such cells formed a layer above progenitor CTBs and expressed transcriptomic profiles related to defense against physical stress and pathogens. Moreover, SC-CTB interacts with EVTs and shows a secretion profile that may control their migration, which contrasts with EVT invasion in the villous region. The authors conclude that their findings provide novel insights into CTB behavior and differentiation at specific locations in the human placenta.

    Overall, this study is novel and addresses an important and uninvestigated question utilizing scRNA-seq and elegant computational approaches. I consider that the field will benefit from this research.

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  4. Reviewer #3 (Public Review):

    The authors have studied the transcriptome of the smooth chorion. The paper is of potential interest but would be improved by analysing from earlier in gestation as it does not indicate how the chorion laeve is formed from the regressing villi.

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