Multi-omics network analysis on samples from sequential biopsies reveals vital role of proliferation arrest for Macrosteatosis related graft failure in rats after liver transplantation

Zhengtao Liu; Wenchao Wang; Xiang Li; Junsheng Zhao; Hai Zhu; Shuping Que; Yong He; Jun Xu; Lin Zhou; Adil Mardinoglu; Shusen Zheng

doi:10.1016/j.ygeno.2023.110748

Multi-omics network analysis on samples from sequential biopsies reveals vital role of proliferation arrest for Macrosteatosis related graft failure in rats after liver transplantation

Genomics. 2023 Nov;115(6):110748. doi: 10.1016/j.ygeno.2023.110748. Epub 2023 Nov 19.

Authors

Zhengtao Liu¹, Wenchao Wang², Xiang Li², Junsheng Zhao³, Hai Zhu⁴, Shuping Que⁵, Yong He², Jun Xu⁶, Lin Zhou⁷, Adil Mardinoglu⁸, Shusen Zheng⁹

Affiliations

¹ Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310015, Zhejiang, China; NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Shulan Hospital (Hangzhou), Hangzhou 310 000, China. Electronic address: liuzhengtao@zjsru.edu.cn.
² NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
³ Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310015, Zhejiang, China.
⁴ NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
⁵ DingXiang Clinics, Hangzhou 310 000, China.
⁶ Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
⁷ NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
⁸ Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK; Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden. Electronic address: adilm@scilifelab.se.
⁹ Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310015, Zhejiang, China; NHC Key Laboratory of Combined Multi-Organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Laboratory of Organ Transplantation, Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Shulan Hospital (Hangzhou), Hangzhou 310 000, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China. Electronic address: shusenzheng@zju.edu.cn.

PMID: 37984718
DOI: 10.1016/j.ygeno.2023.110748

Abstract

To investigate the molecular impact of graft MaS on post-transplant prognosis, based on multi-omics integrative analysis. Rats were fed by methionine-choline deficient diet (MCD) for MaS grafts. Samples were collected from grafts by sequential biopsies. Transcriptomic and metabolomic profilings were assayed. Post-transplant MaS status showed a close association with graft failure. Differentially expressed genes (DEGs) for in-vivo MaS were mainly enriched on pathways of cell cycle and DNA replication. Post-transplant MaS caused arrests of graft regeneration via inhibiting the E2F1 centered network, which was confirmed by an in vitro experiment. Data from metabolomics assays found insufficient serine/creatine which is located on one‑carbon metabolism was responsible for MaS-related GF. Pre-transplant MaS caused severe fibrosis in long-term survivors. DEGs for grafts from long-term survivors with pre-transplant MaS were mainly enriched in pathways of ECM-receptor interaction and focal adhesion. Transcriptional regulatory network analysis confirmed SOX9 as a key transcription factor (TF) for MaS-related fibrosis. Metabolomic assays found elevation of aromatic amino acid (AAA) was a major feature of fibrosis in long-term survivors. Graft MaS in vivo increased post-transplant GF via negative regulations on graft regeneration. Pre-transplant MaS induced severe fibrosis in long-term survivors via activations on ECM-receptor interaction and AAA metabolism.

Keywords: Liver transplantation; Macrosteatosis; Mechanism; Metabonomic; Prognosis; Transcriptomics.

MeSH terms

Animals
Biopsy
Cell Proliferation
Fibrosis
Liver
Liver Transplantation*
Multiomics
Rats