Embryo-derive TNF promotes decidualization via fibroblast activation

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    The authors provide novel evidence for a connection between fibroblast activation and eutherian stromal decidualization. This important work substantially advances our understanding of decidua biology and its contribution to pregnancy. The authors are using solid evidence to support the findings. The methodology includes in vivo mouse and human stroma cells is broadly supports the claims with only minor weaknesses.

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Abstract

Decidualization is a process in which endometrial stromal fibroblasts differentiate into specialized secretory decidual cells and essential for the successful establishment of pregnancy. The underlying mechanism during decidualization still remains poorly defined. Because decidualization and fibroblast activation share similar characteristics, this study was to examine whether fibroblast activation is involved in decidualization. In our study, fibroblast activation-related markers are obviously detected in pregnant decidua and under in vitro decidualization. ACTIVIN A secreted under fibroblast activation promotes in vitro decidualization. We showed that arachidonic acid released from uterine luminal epithelium can induce fibroblast activation and decidualization through PGI 2 and its nuclear receptor PPARδ. Based on the significant difference of fibroblast activation-related markers between pregnant and pseudopregnant mice, we found that embryo-derived TNF promotes CPLA phosphorylation and arachidonic acid release from luminal epithelium. Fibroblast activation is also detected under human in vitro decidualization. Similar arachidonic acid-PGI 2 -PPARδ-ACTIVIN A pathway is conserved in human endometrium. Collectively, our data indicate that embryo-derived TNF promotes CPLA phosphorylation and arachidonic acid release from luminal epithelium to induce fibroblast activation and decidualization.

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  1. Author Response

    Reviewer #2 (Public Review):

    The idea that decidualization is related to or evolved from wound healing, including fibroblast activation, is old, going back all the way to Creighton 1878 who pointed to the similarity between granulation tissue and decidual tissue, and is supported by the fact that embryo implantation is a compensated form of the endometrial lesion. Nevertheless, the mechanistic connection between FB activation and decidualization is an important fact necessary for understanding decidualization, a fact that is reflected in previous work, for instance, Kim et al., 1999 (Hum Reprod 14 Suppl 2), their reference 20, and Oliver et al., 1999 (Humn Reprod 14), their reference 56 a.o.m. More specifically, a recent single-cell study of in vitro decidualization has shown that a myofibroblast-like cell state is a …

  2. eLife assessment

    The authors provide novel evidence for a connection between fibroblast activation and eutherian stromal decidualization. This important work substantially advances our understanding of decidua biology and its contribution to pregnancy. The authors are using solid evidence to support the findings. The methodology includes in vivo mouse and human stroma cells is broadly supports the claims with only minor weaknesses.

  3. Reviewer #1 (Public Review):

    This manuscript provides evidence of a new pathway of endometrial decidualization through COX2-PGI2-PPARδ through fibroblast activation in response to embryo- derive TNFα, conserved in both mice and humans. This is an interesting finding that sheds light on the understanding of the decidua contribution to pregnancy.

    The major inconvenience is how the authors perform the experiments and how they expose their findings. The work needs to be completely rewritten, starting with a clear abstract, with an interconnected introduction, using a defined objective, explaining which organisms/tissues/cells are used in each experiment, the sample size and replicates should be specified in each experiment, and ending with a strong conclusion.

  4. Reviewer #2 (Public Review):

    The idea that decidualization is related to or evolved from wound healing, including fibroblast activation, is old, going back all the way to Creighton 1878 who pointed to the similarity between granulation tissue and decidual tissue, and is supported by the fact that embryo implantation is a compensated form of the endometrial lesion. Nevertheless, the mechanistic connection between FB activation and decidualization is an important fact necessary for understanding decidualization, a fact that is reflected in previous work, for instance, Kim et al., 1999 (Hum Reprod 14 Suppl 2), their reference 20, and Oliver et al., 1999 (Humn Reprod 14), their reference 56 a.o.m. More specifically, a recent single-cell study of in vitro decidualization has shown that a myofibroblast-like cell state is a transient state in …

  5. Reviewer #3 (Public Review):

    This manuscript postulates that uterine stroma cells undergo a stage of activation between the resting state and the differentiated decidual state in order to support embryo implantation. Using in vivo mouse and in vitro mouse and human stroma cells they demonstrate that during decidualization the stroma cells express the marker genes for activated stroma. They then trace an axis from the embryo-producing TNF to prostaglandin production and activin A that is required for this process. They propose data to show that activation of the stroma is altered in infertility due to fetal trisomy 16.

    The strengths of this manuscript are:

    1. This is a comprehensive study using both in vivo and in vitro studies and in both mouse and human stroma cells.
    2. The experiments use a combination of ligands, agonists, and …