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

Junaid Afzal; Wenqiang Du; Ashkan Novin; Yamin Liu; Khadija Wali; Anarghya Murthy; Ashley Garen; Gunter Wagner; Kshitiz

doi:10.3389/fcell.2022.927631

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

Front Cell Dev Biol. 2022 Sep 6:10:927631. doi: 10.3389/fcell.2022.927631. eCollection 2022.

Authors

Junaid Afzal¹, Wenqiang Du², Ashkan Novin², Yamin Liu², Khadija Wali², Anarghya Murthy², Ashley Garen², Gunter Wagner^{3

4}, Kshitiz^{2

4}

Affiliations

¹ Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, CA, United States.
² Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT, United States.
³ Department of Ecology and Evolution, Yale University West Campus, West Haven, CT, United States.
⁴ Systems Biology Institute, Yale University, West Haven, CT, United States.

Abstract

Multiple parallels exist between placentation and cancer dissemination at molecular, cellular, and anatomical levels, presenting placentation as a unique model to mechanistically understand the onset of cancer metastasis. In humans, interaction of placenta and the endometrium results eventually in deep invasion of placental extravillous trophoblasts (EVTs) into the maternal stroma, a process similar to stromal trespass by disseminating carcinoma cells. In anticipation of implantation, endometrial fibroblasts (ESFs) undergo a process called decidualization during the secretory phase of the menstrual cycle. Decidualization, among other substantial changes associated with ESF differentiation, also involves a component of fibroblast activation, and myofibroblast transformation. Here, using traction force microscopy, we show that increased cellular contractility in decidualized ESFs is reversed after interaction with EVTs. We also report here the large changes in energetic state of ESFs upon decidualization, showing increased oxidative phosphorylation, mitochondrial competency and ATP generation, as well as enhanced aerobic glycolysis, presenting mechanical contractility and energetic state as new functional hallmarks for decidualization. These energetic changes accompanying the marked increase in contractile force generation in decidualization were reduced in the presence of EVTs. We also show that increase in decidual contractility and mechanical resistance to invasion is achieved by SRF-MRTF transcriptional activation, achieved via increased phosphorylation of fibroblast-specific myosin light chain 9 (MYL9). EVT induced paracrine secretion of Heparin Binding Epidermal Growth Factor (HBEGF), a potent MAPK activator, which shifts the balance of SRF association away from MRTF based transcription, reducing decidual ESF contractility and mechanical resistance to placental invasion. Our results identify a new axis of intercellular communication in the placental bed modulating stromal force generation and resistance to invasion with concurrent downregulation of cellular energetics. These findings have important implications for implantation related disorders, as well as stromal control of cancer dissemination.

Keywords: SRF-Mrtf/Tcf axis; cancer-stroma crosstalk; cell-cell communication; contractility; energetics; fetal maternal interface; paracrine HB-EGF signaling; placental invasion.