Novel ceRNA network construction associated with programmed cell death in acute rejection of heart allograft in mice

Yiwen Guo; Yixi Zhang; Jia Yu; Yuqi Dong; Zhitao Chen; Chuchen Zhu; Xitao Hong; Zhonghao Xie; Min Zhang; Shuai Wang; Yichen Liang; Xiaoshun He; Weiqiang Ju; Maogen Chen

doi:10.3389/fimmu.2023.1184409

Novel ceRNA network construction associated with programmed cell death in acute rejection of heart allograft in mice

Front Immunol. 2023 Sep 11:14:1184409. doi: 10.3389/fimmu.2023.1184409. eCollection 2023.

Authors

Yiwen Guo^{1

2

3}, Yixi Zhang⁴, Jia Yu^{1

2

3}, Yuqi Dong^{1

2

3}, Zhitao Chen^{1

2

3}, Chuchen Zhu^{1

2

3}, Xitao Hong^{1

2

3}, Zhonghao Xie^{1

2

3}, Min Zhang^{1

2

3}, Shuai Wang^{1

2

3}, Yichen Liang^{1

2

3}, Xiaoshun He^{1

2

3}, Weiqiang Ju^{1

2

3}, Maogen Chen^{1

2

3}

Affiliations

¹ The First Affiliated Hospital, Sun Yat-Sen University, Organ Transplant Centre, Guangzhou, China.
² Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China.
³ Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China.
⁴ Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Abstract

Background: T cell-mediated acute rejection(AR) after heart transplantation(HT) ultimately results in graft failure and is a common indication for secondary transplantation. It's a serious threat to heart transplant recipients. This study aimed to explore the novel lncRNA-miRNA-mRNA networks that contributed to AR in a mouse heart transplantation model.

Methods: The donor heart from Babl/C mice was transplanted to C57BL/6 mice with heterotopic implantation to the abdominal cavity. The control group was syngeneic heart transplantation with the same kind of mice donor. The whole-transcriptome sequencing was performed to obtain differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs) and lncRNAs (DElncRNAs) in mouse heart allograft. The biological functions of ceRNA networks was analyzed by GO and KEGG enrichment. Differentially expressed ceRNA involved in programmed cell death were further verified with qRT-PCR testing.

Results: Lots of DEmRNAs, DEmiRNAs and DElncRNAs were identified in acute rejection and control after heart transplantation, including up-regulated 4754 DEmRNAs, 1634 DElncRNAs, 182 DEmiRNAs, and down-regulated 4365 DEmRNAs, 1761 DElncRNAs, 132 DEmiRNAs. Based on the ceRNA theory, lncRNA-miRNA-mRNA regulatory networks were constructed in allograft acute rejection response. The functional enrichment analysis indicate that the down-regulated mRNAs are mainly involved in cardiac muscle cell contraction, potassium channel activity, etc. and the up-regulated mRNAs are mainly involved in T cell differentiation and mononuclear cell migration, etc. The KEGG pathway enrichment analysis showed that the down-regulated DEmRNAs were mainly enriched in adrenergic signaling, axon guidance, calcium signaling pathway, etc. The up-regulated DEmRNAs were enriched in the adhesion function, chemokine signaling pathway, apoptosis, etc. Four lncRNA-mediated ceRNA regulatory pathways, Pvt1/miR-30c-5p/Pdgfc, 1700071M16Rik/miR-145a-3p/Pdgfc, 1700071M16Rik/miR-145a-3p/Tox, 1700071M16Rik/miR-145a-3p/Themis2, were finally validated. In addition, increased expression of PVT1, 1700071M16Rik, Tox and Themis2 may be considered as potential diagnostic gene biomarkers in AR.

Conclusion: We speculated that Pvt1/miR-30c-5p/Pdgfc, 1700071M16Rik/miR-145a-3p/Pdgfc, 1700071M16Rik/miR-145a-3p/Tox and 1700071M16Rik/miR-145a-3p/Themis2 interaction pairs may serve as potential biomarkers in AR after HT.

Keywords: acute rejection (AR); ceRNA; heart transplant; lncRNA; mRNA; microRNA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allografts
Animals
Apoptosis
Disease Models, Animal
Heart Transplantation* / adverse effects
Humans
Mice
Mice, Inbred C57BL
RNA, Long Noncoding* / genetics
Tissue Donors

Substances

RNA, Long Noncoding

Grants and funding

Supported by grants as follows: National Natural Science Foundation of China (81401324 and 81770410), the Guangdong Provincial Key Laboratory Construction Projection on Organ Donation and Transplant Immunology (2013A061401007, 2017B030314018 and 2020B1212060026).