Exosomes released from decidual macrophages deliver miR-153-3p, which inhibits trophoblastic biological behavior in unexplained recurrent spontaneous abortion.

Spontaneous abortion is a common disease in human pregnancy. Increasing evidence suggests that proper function of trophoblasts and immune balance of the maternal-fetal interface are crucial for successful pregnancy. Macrophages are involved in the maternal-fetal immune microenvironment. However, mechanisms associated with how macrophages impair trophoblasts' function in spontaneous abortion remain to be explored. Firstly, the characteristics of the isolated macrophage-derived exosomes were verified by TEM and Western blot. Then, we established the co-culture of macrophage-derived exosomes with trophoblasts, and explored the role of the exosomes in trophoblasts. Moreover, expression of miR-153-3p in the macrophage-derived exosomes was detected. A miR-153-3p mimic was transfected into trophoblasts to investigate its function in the biological functions of trophoblast cells. MRNA and protein expressions were detected by qRT-PCR and Western blot. CCK8 assay was performed to measure cell proliferation and Transwell assay was utilized to examine migration of trophoblasts. Compared with those in normal pregnant women, decidual macrophage-derived exosomes from unexplained recurrent spontaneous abortion (URSA) patients suppressed the proliferation and migration of trophoblast cells through the IDO/STAT3 pathway. MiR-153-3p was highly expressed in exosomes released from decidual macrophages of URSA patients. Transfecting miR-153-3p mimics into trophoblast cells directly inhibited IDO genes, which suppressed STAT3 pathway activation, regulating the biological behavior of trophoblast cells. This study outlines the role of decidual macrophage-derived exosomal miR-153-3p in successful pregnancy maintenance, paving a new approach for the development of novel treatments for URSA.

Ying X ，Jin X ，Zhu Y ，Liang M ，Chang X ，Zheng L ... -  《-》

Exosome-delivered miR-410-3p reverses epithelial-mesenchymal transition, migration and invasion of trophoblasts in spontaneous abortion.

Chen ZY ，Li Z ，Zong Y ，Xia B ，Luo SP ，Deng GP ，Gao J ... -  《-》

Dysregulated expression of IDO may cause unexplained recurrent spontaneous abortion through suppression of trophoblast cell proliferation and migration.

Zong S ，Li C ，Luo C ，Zhao X ，Liu C ，Wang K ，Jia W ，Bai M ，Yin M ，Bao S ，Guo J ，Kang J ，Duan T ，Zhou Q ... -  《Scientific Reports》

Decidual stromal cells-derived exosomes incurred insufficient migration and invasion of trophoblast by disturbing of β-TrCP-mediated snail ubiquitination and degradation in unexplained recurrent spontaneous abortion.

Xiong M ，Wang Q ，Zhang X ，Wen L ，Zhao A ... -  《-》

Decidual IDO(+) macrophage promotes the proliferation and restricts the apoptosis of trophoblasts.

Indoleamine 2, 3-dioxygenase (IDO), a tryptophan-catabolizing enzyme, is essential in physiological immunoregulation. The present research was conducted to elucidate the expression and roles of IDO in decidual macrophages (dMφ) during early pregnancy. Here, we observed a remarkable decrease of IDO+ dMφ from patients with unexplained recurrent spontaneous abortion (URSA). IDO+ dMφ displayed M2 phenotype with higher CD206, CD209 and CD163, and lower CD86. Interestingly, treatment with 1-methyl-d-tryptophan (1-MT, an IDO pathway inhibitor) led to the M1 bias of dMφ. Further analysis of the cytokine array and the qPCR showed decreased levels of trophoblast proliferation or invasion-related molecules (e.g., CXCL12 and BMP2) in 1-MT-treated dMφ. The data of co-culture system showed that 1-MT-pretreated dMφ decreased the proliferation and the expression of Ki-67 and Bcl-2, and increased cell apoptosis of HTR-8/Snveo cells. Additionally, the expression of IDO in U937 cells was up-regulated by decidual stromal cells (DSC) and HTR-8/Snveo cells in vitro, as well as estradiol and medroxyprogesterone. These data suggest that endocrine environment, DSC and trophoblasts should contribute to the high level of IDO in dMφ, and IDO+ dMφ with M2 dominant phenotype promote the survival of trophoblasts during early pregnancy. The abnormal lower level of IDO should trigger the dysfunction of dMφ, further suppress the survival of trophoblasts and increase the risk of miscarriage.

Huang HL ，Yang HL ，Lai ZZ ，Yang SL ，Li MQ ，Li DJ ... -  《-》