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Introduction <p>G protein-coupled estrogen receptor (GPER) is a heptahelix estrogen-binding G protein-coupled receptor, and a potential therapeutic target for estrogen-related cancers and diseases. Recently, GPER has been recognized as a key mechano-regulator, but the effects on cell adhesion, spreading, morphology, migration, and differentiation are inconsistent or even contradicting in literature, due to the variations across cell lines and complex crosstalks with ER, and non-genomic actions of other hormones. Here, we focus on&#xa0;investigating the GPER effect on mesenchymal stem cell (MSC) mechanotransduction and differentiation.</p> Methods <p>MSCs treated by synthetic agonist G1 and untreated cells were cultured on fibronectin-coated surfaces. Cell morphology and cytoskeletons were&#xa0;characterized by staining and imaging.&#xa0;RhoA signaling was evaluated by western blot assays.&#xa0;Cell migration was studied by both chemokinesis and chemotaxis experiments. MSC adipogenesis and osteogenesis were evaluated after two-week differentiation. In particular, since micropatterns have been widely used to mimic extracellular matrix (ECM) cues, modulate MSC mechanotransduction and differentiation, we investigate the GPER effect on both single-cell and sub-cellular fibronectin microline patterns prepared by microcontact printing.</p> Results <p>GPER activation regulates cytoskeleton organization, with reduced cell polarization and thinner ventral stress fibers; reduces MSC migration speed; significantly promotes osteogenesis and inhibits adipogenesis. Cell elongation by micropatterns and the reduction of cell polarization by GPER coexist in a sophisticated interplay.</p> Conclusions <p>GPER directly mediates MSC mechanotransduction by RhoA inactivation, while its sustained effect on MSC differentiation promotes osteogenesis and inhibits adipogenesis despite reduced cell polarization and tension, suggesting potential mechanisms other than RhoA signaling. Our findings pave the way towards a deep understanding of GPER’s role and its interplay with ECM cues in mechanotransduction and differentiation, which will be important for developing GPER as a new therapeutic target, as well as considering its important effects in stem cell therapies and hormonal therapies.</p>

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G Protein-Coupled Estrogen Receptor Regulates Mesenchymal Stem Cell Mechanotransduction and Differentiation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月11日

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  • Hao Wang,
  • Ofra Ben Menachem-Zidon,
  • Ashish Pandey,
  • Yue Xiao,
  • Nanzhong Deng,
  • Xiaojie Shi,
  • Amparo Ruiz,
  • Yi Ye,
  • Haogang Cai

摘要

Introduction

G protein-coupled estrogen receptor (GPER) is a heptahelix estrogen-binding G protein-coupled receptor, and a potential therapeutic target for estrogen-related cancers and diseases. Recently, GPER has been recognized as a key mechano-regulator, but the effects on cell adhesion, spreading, morphology, migration, and differentiation are inconsistent or even contradicting in literature, due to the variations across cell lines and complex crosstalks with ER, and non-genomic actions of other hormones. Here, we focus on investigating the GPER effect on mesenchymal stem cell (MSC) mechanotransduction and differentiation.

Methods

MSCs treated by synthetic agonist G1 and untreated cells were cultured on fibronectin-coated surfaces. Cell morphology and cytoskeletons were characterized by staining and imaging. RhoA signaling was evaluated by western blot assays. Cell migration was studied by both chemokinesis and chemotaxis experiments. MSC adipogenesis and osteogenesis were evaluated after two-week differentiation. In particular, since micropatterns have been widely used to mimic extracellular matrix (ECM) cues, modulate MSC mechanotransduction and differentiation, we investigate the GPER effect on both single-cell and sub-cellular fibronectin microline patterns prepared by microcontact printing.

Results

GPER activation regulates cytoskeleton organization, with reduced cell polarization and thinner ventral stress fibers; reduces MSC migration speed; significantly promotes osteogenesis and inhibits adipogenesis. Cell elongation by micropatterns and the reduction of cell polarization by GPER coexist in a sophisticated interplay.

Conclusions

GPER directly mediates MSC mechanotransduction by RhoA inactivation, while its sustained effect on MSC differentiation promotes osteogenesis and inhibits adipogenesis despite reduced cell polarization and tension, suggesting potential mechanisms other than RhoA signaling. Our findings pave the way towards a deep understanding of GPER’s role and its interplay with ECM cues in mechanotransduction and differentiation, which will be important for developing GPER as a new therapeutic target, as well as considering its important effects in stem cell therapies and hormonal therapies.