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EXPERT REVIEW
Year : 2020  |  Volume : 4  |  Issue : 1  |  Page : 7-10

Single-cell RNA expression profiling of ACE2 and AXL in the human maternal–Fetal interface


Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China

Date of Submission14-Feb-2020
Date of Acceptance17-Feb-2020
Date of Web Publication18-Feb-2020

Correspondence Address:
Li-Ping Jin
Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204
China
Tao Duan
Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.278679

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  Abstract 


2019 novel coronavirus disease has resulted in thousands of critically ill patients in China, which is a serious threat to people's life and health. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was reported to share the same receptor, angiotensin-converting enzyme 2 (ACE2), with SARS-CoV. Here, based on the public single-cell RNA-sequencing database, we analyzed the mRNA expression profile of putative receptor ACE2 and AXL receptor tyrosine kinase (AXL) in the early maternal–fetal interface. The result indicates that the ACE2 has very low expression in the different cell types of early maternal–fetal interface, except slightly high in decidual perivascular cells cluster 1 (PV1). Interestingly, we found that the Zika virus (ZIKV) receptor AXL expression is concentrated in perivascular cells and stromal cells, indicating that there are relatively more AXL-expressing cells in the early maternal–fetal interface. This study provides a possible infection route and mechanism for the SARS-CoV-2- or ZIKV-infected mother-to-fetus transmission disease, which could be informative for future therapeutic strategy development.

Keywords: 2019 Novel Coronavirus Disease; ACE2; AXL; Maternal–Fetal Interface; Severe Acute Respiratory Syndrome Coronavirus 2; Vertical Transmission


How to cite this article:
Zheng QL, Duan T, Jin LP. Single-cell RNA expression profiling of ACE2 and AXL in the human maternal–Fetal interface. Reprod Dev Med 2020;4:7-10

How to cite this URL:
Zheng QL, Duan T, Jin LP. Single-cell RNA expression profiling of ACE2 and AXL in the human maternal–Fetal interface. Reprod Dev Med [serial online] 2020 [cited 2020 Nov 26];4:7-10. Available from: https://www.repdevmed.org/text.asp?2020/4/1/7/278679



Severe infection by severe acute respiratory syndrome -coronavirus 2 (SARS-CoV-2) could result in acute respiratory distress syndrome and sepsis, causing death in approximately 15% of the infected individuals.[1] This virus can spread mainly through respiratory droplets and contact transmission. Recently, Chen et al. have found that there is currently no evidence for intrauterine infection caused by vertical transmission in women who develop 2019 novel coronavirus disease pneumonia in late pregnancy.[2] However, it has not been reported that the mechanism of why SARS-CoV-2 cannot cause vertical transmission from mother to fetus.

Some groups have identified that angiotensin-converting enzyme 2 (ACE2) could be the surface receptor of sensitive cells for SARS-CoV-2, although the binding strength of SARS-CoV-2 with ACE2 is weaker than that of SARS-Cov with ACE2.[3],[4] We all know that the expression and distribution of the receptor will decide the route of virus infection. The maternal–fetal interface is a complex microenvironment with multiple types of cells,[5] and RNA profiling or protein expression analysis is based on bulk tissue analysis with no way to elucidate the ACE2 expression in each cell type of the human maternal–fetal interface. The single-cell RNA-sequencing technology enables us to study the ACE2 expression in each cell type at single-cell resolution,[6] and this method will help us to clearly illustrate the infection route of SARS-CoV-2 and other viruses in the maternal–fetal interface.

Previous work had built up the online database for combined single-cell transcriptome profiles from the early maternal–fetal interface (11 deciduas and 5 placentas from 6–14 gestational weeks) and 6 matched peripheral blood mononuclear cell datasets.[7] It identified 33 transcriptionally distinct cell clusters based on their marker gene expression profile.[7] The cell cluster map was visualized using Uniform Manifold Approximation and Projection, as shown in [Figure 1]a and [Figure 1]b, and the represented cell-type marker expressions are demonstrated in [Figure 1]c and [Figure 1]d.
Figure 1:UMAP visualization of cell types at the early maternal-fetal interface. (a) Placental and decidual cell cluster analysis visualized by UMAP. Colors indicate cell type. (b) Origin of droplet cells in a by tissue (blood, decidua, and placenta). (c-h) UMAP visualization and violin plots of expression for perivascular cell-type-specific marker genes (MGP) (c and d), ACE2 (e and f), and AXL (g and h) in distinct cell clusters of the early maternal-fetal interface. UMAP: Uniform Manifold Approximation and Projection; DC: Dendritic cells; dM: Decidual macrophages; dS: Decidual stromal cells; Endo: Endothelial cells; Epi: Epithelial glandular cells; F: Fibroblasts; HB: Hofbauer cells; PV: Perivascular cells; SCT: Syncytiotrophoblast; VCT: Villous cytotrophoblast; EVT: Extravillous trophoblast; NK: Natural killer cells.

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In the current work, we analyzed the cell-type-specific expression pattern of ACE2. ACE2 is expressed very low in all kinds of maternal–fetal interface cells. The majority of the ACE2-expressing cells are perivascular cells cluster 1 (PV1), and other ACE2-expressing cells include syncytiotrophoblast cells, decidual stromal cells (dS), and epithelial glandular cells [Figure 1]e and 1f]. However, their ACE2-expressing cell ratio is very low. To further understand the specificity of ACE2-expressing PV1, we found that ACE2-expressing PV1 only expressed 8 (CAV2, GSN, STOM, APOE, HSPA8, PPIA, IFITM3, and PPIB) of 35 viral process-related genes that are highly expressed in type II alveolar cells of lung.[8] It seems that SARS-CoV-2 has not evolved cleverly enough to hijack PV1 cluster cells for its transmission; we speculate that there may be no potentially susceptible population for SARS-CoV-2 in the early maternal–fetal interface. This maybe one of the reasons that why SARS-CoV-2 cannot be vertically transmitted from mother to fetus among the nine reported cases.[2]

Zika virus (ZIKV) is a mosquito-borne flavivirus that has rapidly spread to over thirty countries and causes illness with symptoms of fever, joint pain, and conjunctivitis.[9] ZIKV is transmitted through several routes, including mosquito bites, sexual contact, and blood transfusion.[10] Most notably, ZIKV can be vertically transmitted from an infected mother to the developing fetus in utero, resulting in adverse pregnancy outcomes.[11] Mounting evidence indicates that infection in early gestation can lead to miscarriage, stillbirth, and intrauterine growth restriction.[12] It has been identified that ZIKV infects the placenta and reaches the fetal compartment with the help of viral entry cofactors (AXL, Tyro3, and TIM1), with AXL playing a major role.[13] Next, we analyzed the cell-type-specific expression pattern of AXL. AXL is expressed highly in a small part of early maternal–fetal interface cells. The majority of the AXL-expressing cells are perivascular cells (PV) and dS, and other AXL-expressing cells include fibroblasts, dendritic cells, and decidual macrophages [Figure 1]g and 1h]. It seems that the ZIKV may have evolved cleverly enough to hijack PV and dS cluster cells for its reproduction and transmission. This result is highly consistent with that of previous reports.[13],[14] This might also explain the observation that why the ZIKV can be vertically transmitted from mother to fetus.

Above all, in the current study, we report the RNA expression profile of ACE2 in the human early maternal–fetal interface at single-cell resolution. Our analysis suggested that the expression of ACE2 is very low in all kinds of early maternal–fetal interface cells, relatively higher in PV, and the expression of AXL is high in a small part of early maternal–fetal interface cells, such as PV and dS. Hence, we speculate that the ratio of SARS-CoV-2-infected mother-to-fetus transmission will be significantly lower than that of ZIKV, because the expression of ACE2 is very low in early maternal–fetal interface cells. This conclusion will help to avoid unnecessary panic among the general public.

For the suspected cases vertically transmitted from SARS-CoV-2-infected mother to fetus reported on February 5, 2020, in Wuhan, we speculate that the reason is more likely the neonatal contact transmission, because maternal secretions may be in contact with the child during childbirth. Furthermore, it remains unknown whether there are other receptors responsible for the SARS-CoV-2 infection. Future work needs to explore the new receptors of SARS-CoV-2.


  Methods Top


Public datasets deposited at ArrayExpress (E-MTAB-6678) were used for bioinformatics analysis.[7] The expression data for maternal–fetal interface are also available for interactive browsing online at http://data.teichlab.org.

Financial support and sponsorship

This study was supported by the Key Program of the National Natural Science Foundation of China (81730039), the National Natural Science Foundation of China (81671460, 81871167), the National Key Research and Development Program of China (2017YFC1001401), Shanghai Municipal Medical and Health Discipline Construction Projects (2017ZZ02015), the National Basic Research Program of China (2015CB943300), the Program for Shanghai leaders to Li-Ping Jin, and the Natural Science Foundation of Shanghai (18ZR1430000) to Qingliang Zheng.

Conflicts of interest

There are no conflicts of interest.



 
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Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records. Lancet 2020. [Ahead of print]. doi: 10.1016/S0140-6736(20) 30360-3.  Back to cited text no. 2
    
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Li W, Sui J, Huang IC, Kuhn JH, Radoshitzky SR, Marasco WA, et al. The S proteins of human coronavirus NL63 and severe acute respiratory syndrome coronavirus bind overlapping regions of ACE2. Virology 2007;367:367-74. doi: 10.1016/j.virol.2007.04.035.  Back to cited text no. 4
    
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