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. 2022 Sep 6;11(18):2772.
doi: 10.3390/cells11182772.

Exporting Proteins Associated with Senescence Repair via Extracellular Vesicles May Be Associated with Early Pregnancy Loss

Yi Zhang  1 , Yunhui Tang  2 , Xinyi Sun  1 , Matt Kang  1 , Min Zhao  3 , Jiayi Wan  4 , Qi Chen  1
Affiliations

Exporting Proteins Associated with Senescence Repair via Extracellular Vesicles May Be Associated with Early Pregnancy Loss

Yi Zhang et al. Cells. .

Abstract

Introduction: Dysfunction of placental development is involved in early pregnancy loss. Senescent changes have been seen in missed miscarriage, one type of pregnancy loss. Extracellular vesicles (EVs) have been widely implicated in the pathogenesis of diseases. In this study, we investigated the protein profiles in placental EVs derived from missed miscarriage in comparison with healthy pregnancy. We also investigated whether cargos packed into EVs are involved in the dysfunctional development of the placenta seen in missed miscarriage.

Methods: Proteomic analysis of placental EVs derived from healthy and missed-miscarriage placentae was performed. Three senescence-repair-associated proteins, replication protein A-70 (RPA-70), proteasome activator subunit-4 (PMSE-4), and protein activated kinase-2, (PAK-2) were examined in placental EVs and placentae, and in placental explants that had been treated with or without GW4869, by western blotting and immunohistochemistry.

Results: The total number of proteins associated with placental EVs was not different between the two groups. However, there were 106 and 151 abundantly expressed proteins associated with placental micro- or nano-EVs from missed miscarriage in comparison with EVs from controls. Of these abundant proteins, 59 and 81 proteins in placental micro- or nano-EVs, respectively, are associated with DNA damage/repair and cell death/survival. We further found higher levels of three senescence-repair-associated proteins (RPA-70, PMSE-4, and PAK-2) associated with placental EVs, but lower levels of these proteins in missed-miscarriage placentae. Regarding inhibition of EV formation or release by GW4869, we found that the expression of these three proteins was higher in GW4869-treated placental explants from missed miscarriage.

Discussion: Our data may suggest that "inadvertently" sorting of cargos and exporting proteins associated with senescence-repair by placental EVs may be associated with the dysfunction of placental development seen in missed miscarriage.

Keywords: inhibitor of EV formation; missed miscarriage; placental EVs; placental development; proteomics; senescence-repair; sorting of cargo.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The concentration of proteins in micro-EVs and nano-EVs from missed miscarriage and healthy placentae.
Figure 2
Figure 2
The number of proteins in placental micro-EVs (A) or nano-EVs (B) from missed miscarriage and healthy pregnancy.
Figure 3
Figure 3
The heatmap of the proteins in placental EVs from missed miscarriage and healthy pregnancy.
Figure 4
Figure 4
The abundantly expressed proteins in micro-EVs (A) and nano-EVs (B) from missed-miscarriage and healthy placentae.
Figure 5
Figure 5
The representative western blotting images showing the high levels of RPA-70 (A) and PAK-2 (B) in placental micro-EVs, and high levels of PSME-4 (C) placental nano-EVs derived from missed-miscarriage placentae, measured by a semiquantitative analysis (D). (MM: missed miscarriage, NC: control).
Figure 5
Figure 5
The representative western blotting images showing the high levels of RPA-70 (A) and PAK-2 (B) in placental micro-EVs, and high levels of PSME-4 (C) placental nano-EVs derived from missed-miscarriage placentae, measured by a semiquantitative analysis (D). (MM: missed miscarriage, NC: control).
Figure 6
Figure 6
The representative immunohistochemistry images showing the lower expression of RPA-70 (A), PSME-4 (B), and PAK-2 (C) in missed-miscarriage placentae (b) and control placentae (a), measured by a semiquantitative analysis (D) (magnification: ×400).
Figure 6
Figure 6
The representative immunohistochemistry images showing the lower expression of RPA-70 (A), PSME-4 (B), and PAK-2 (C) in missed-miscarriage placentae (b) and control placentae (a), measured by a semiquantitative analysis (D) (magnification: ×400).
Figure 7
Figure 7
The representative immunohistochemistry images showing the expression of RPA-70 (A), PSME-4 (B), and PAK-2 (C) in missed-miscarriage placental explants that had been treated with (a) or without (b) GW4869, measured by a semiquantitative analysis (D) (magnification: ×400).
Figure 7
Figure 7
The representative immunohistochemistry images showing the expression of RPA-70 (A), PSME-4 (B), and PAK-2 (C) in missed-miscarriage placental explants that had been treated with (a) or without (b) GW4869, measured by a semiquantitative analysis (D) (magnification: ×400).
See this image and copyright information in PMC

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