1. Academic Validation
  2. GAS6-mediated dialogue between decidual stromal cells and macrophages is essential for early pregnancy maintenance by inducing M2-like polarization and cell proliferation of decidual macrophages

GAS6-mediated dialogue between decidual stromal cells and macrophages is essential for early pregnancy maintenance by inducing M2-like polarization and cell proliferation of decidual macrophages

  • Mol Hum Reprod. 2022 Mar 8;28(3):gaac006. doi: 10.1093/molehr/gaac006.
Jing-Cong Dai 1 Jia-Yan Yang 1 Rui-Qi Chang 2 3 Yan Liang 1 Xiao-Yu Hu 1 Hu Li 1 Shuang You 1 Fan He 2 3 4 Li-Na Hu 2 3 4
Affiliations

Affiliations

  • 1 Obstetrics and Gynecology Department, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 The Center for Reproductive Medicine, Obstetrics and Gynecology Department, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3 Joint International Research Lab for Reproduction and Development, Ministry of Education, Chongqing, China.
  • 4 Reproduction and Stem Cell Therapy Research Center of Chongqing, Chongqing, China.
Abstract

Maternal immunotolerance towards the semi-allogeneic foetus is critical for normal pregnancy (NP). As a secretory protein, growth arrest-specific factor 6 (GAS6) promotes Cancer progression by inducing the conversion of tumour-associated macrophages to an immunosuppressive M2-like phenotype. However, little is known about whether GAS6 regulates decidual macrophages (dMφs) in the early maternal-foetal interface. In this study, first-trimester decidual tissues were obtained from normal pregnant women undergoing elective terminations and patients with miscarriages. The expression of GAS6 and its receptors (AXL, TYRO3 and MERTK) in decidua and GAS6 secretion by decidual stromal cells (DSCs) was measured. Then, we investigated the effect of recombinant human GAS6 (rhGAS6) on dMφs isolated from NP and THP-1 cells, and revealed the underlying mechanism. Both the expression of GAS6 in DSCs and MERTK in dMφs, in addition to GAS6 secretion by DSCs, was found to be significantly decreased in miscarriage patients compared to that in NPs. Additionally, we observed that rhGAS6 polarized dMφs and THP-1 cells towards an M2-like phenotype, as evidenced by the up-regulated CD163 expression. Moreover, rhGAS6 enhanced the clearance of toxic cell-free haemoglobin by dMφs by up-regulating CD163 expression, and rhGAS6 also boosted cell proliferation of dMφs and THP-1 cells. Finally, we demonstrated that rhGAS6 stimulated CD163 expression and cell proliferation by activating the PI3K/Akt signalling pathway. Collectively, these findings suggest that GAS6-mediated dialogue between DSCs and dMφs is crucial for the establishment and maintenance of maternal-foetal immunotolerance, and decreased GAS6 secretion by DSCs may lead to the occurrence of miscarriage in the first trimester.

Keywords

CD163; M2-like polarization; cell proliferation; decidual macrophages; decidual stromal cells; growth arrest-specific factor 6; maternal–foetal interface; miscarriage; pregnancy.

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