Decidual cell differentiation is evolutionarily derived from fibroblast activation

Abstract

What the molecular mechanisms underlying the evolutionary origin of novel cell types are is a major unresolved question in biology. The uterine decidual cell is a novel cell type of placental mammals which serves as the interface between maternal and fetal tissues during pregnancy. In this paper, we investigate two models for the nature of the differentiation of decidual cells: first, that it represents a mesenchymal-epithelial transition (MET), and second, that it evolved from wound-induced fibroblast activation (WIFA). Immunocytochemistry and RNA-seq analysis of decidualizing human endometrial fibroblasts cast doubt on the MET hypothesis and instead demonstrate a similarity between decidualization and fibroblast activation, including a central role for TGFB1. Through single-cell RNA-seq, we found a transient myofibroblast-like cell population in the in vitro differentiation trajectory of human decidual cells and found that these cells represent a pre-decidual state approaching the inferred transcriptomic transition to decidual cells. We propose an evolutionary developmental model wherein the decidual cell is a novel cell type not equivalent to the myofibroblast, but the process of decidual differentiation itself evolved as an endometrial-specific modification to fibroblast activation in response to the wound caused by embryo implantation.

Transposable Elements Continuously Remodel the Regulatory Landscape, Transcriptome, and Function of Decidual Stromal Cells

“…Extant mammals span several major evolutionary transitions during the origins, divergence, and conservation of pregnancy, including the origin of new cell-types in the uterine lining (endometrium), endometrial stromal fibroblasts (ESFs), and decidual stromal cells (DSCs) ( Erkenbrack et al 2018 ; Wu et al 2020 ; Chavan et al 2021 ), which mediate many of the maternal responses to pregnancy. For example, an essential step in the establishment and maintenance of pregnancy is the differentiation (decidualization) of ESFs into DSCs in response to progesterone acting through the progesterone receptor (PGR), the second messenger cyclic AMP (cAMP) acting through protein kinase A (PKA), the transcription factor FOXO1 ( Gellersen and Brosens 2003 ; Kajihara et al 2013 ), and, in some species, to fetal signals ( Gellersen et al 2007 ).…”

Paracrine HB-EGF signaling reduce enhanced contractile and energetic state of activated decidual fibroblasts by rebalancing SRF-MRTF-TCF transcriptional axis

“…In the process, EVTs interact with the decidual endometrial fibroblasts (dESFs) ( Figure 1A ). We have previously reported that decidualization is evolutionarily derived from fibroblast activation ( Wu et al, 2020 ). Indeed, we had found that differentiation of ESFs involves an interim stage which mimics activation of fibroblasts in response to wounding, which gets extended to a larger program of decidualization ( Wu et al, 2020 ).…”

“…We have previously reported that decidualization is evolutionarily derived from fibroblast activation ( Wu et al, 2020 ). Indeed, we had found that differentiation of ESFs involves an interim stage which mimics activation of fibroblasts in response to wounding, which gets extended to a larger program of decidualization ( Wu et al, 2020 ). Early decidualization, therefore, appeared to be mimicking increase in ESF contractility and generation of mechanical forces.…”

“…In recent works, we have shown that decidualization significantly reduces trophoblast invasion, suggesting that the advent of dESFs is an evolutionary response to limit excessive invasion. We have also shown that decidualization as a process has evolved by incorporating a classical fibroblast activation response to wounding ( Wu et al, 2020 ), which occurs in response to the degradation of uterine epithelium by trophoblasts, and their invasion into the maternal stroma.…”

Transposable elements continuously remodel the regulatory landscape, transcriptome, and function of decidual stromal cells

“…Extant mammals span several major evolutionary transitions during the origins, divergence, and conservation of pregnancy, including the origin of new cell-types in the uterine lining (endometrium), endometrial stromal fibroblasts (ESF), and decidual stromal cells (DSC) (Chavan et al, 2021; Erkenbrack et al, 2018; Wu et al, 2020), which mediate many of the maternal responses to pregnancy. For example, an essential step in the establishment and maintenance of pregnancy is the differentiation (decidualization) of ESFs into DSCs in response to progesterone acting through the progesterone receptor (PGR), the second messenger cyclic AMP (cAMP) acting through protein kinase A (PKA), the transcription factor FOXO1 (Gellersen and Brosens, 2003; Kajihara et al, 2013), and, in some species, to fetal signals (Gellersen et al, 2007).…”