PMID- 35340061
OWN - NLM
STAT- MEDLINE
DCOM- 20220922
LR  - 20221229
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 76
IP  - 4
DP  - 2022 Oct
TI  - ATP7B gene therapy of autologous reprogrammed hepatocytes alleviates copper 
      accumulation in a mouse model of Wilson's disease.
PG  - 1046-1057
LID - 10.1002/hep.32484 [doi]
AB  - BACKGROUND AND AIMS: Wilson's disease (WD) is a rare hereditary disorder due to 
      ATP7B gene mutation, causing pathologic copper storage mainly in the liver and 
      neurological systems. Hepatocyte transplantation showed therapeutic potential; 
      however, this strategy is often hindered by a shortage of quality donor cells and 
      by allogeneic immune rejection. In this study, we aimed to evaluate the function 
      and efficacy of autologous reprogrammed, ATP7B gene-restored hepatocytes using a 
      mouse model of WD. APPROACH AND RESULTS: Sufficient liver progenitor cells (LPCs) 
      were harvested by reprogramming hepatocytes from ATP7B(-/-) mice with small 
      molecules, which exhibited strong proliferation and hepatic differentiation 
      capacity in vitro. After lentivirus-mediated mini ATP7B gene transfection and 
      redifferentiation, functional LPC-ATP7B-derived hepatocytes (LPC-ATP7B-Heps) were 
      developed. RNA sequencing data showed that, compared with LPC-green fluorescent 
      protein-Heps (LPC-GFP-Heps) with enrichment of genes that were mainly in pathways 
      of oxidative stress and cell apoptosis, in LPC-ATP7B-Heps under high copper 
      stress, copper ion binding and cell proliferation pathways were enriched. 
      LPC-ATP7B-Heps transplantation into ATP7B(-/-) mice alleviated deposition of 
      excess liver copper with its associated inflammation and fibrosis, comparable 
      with those observed using normal primary hepatocytes at 4 months after 
      transplantation. CONCLUSIONS: We established a system of autologous reprogrammed 
      WD hepatocytes and achieved ATP7B gene therapy in vitro. LPC-ATP7B-Heps 
      transplantation demonstrated therapeutic efficacy on copper homeostasis in a 
      mouse model of WD.
CI  - (c) 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of 
      American Association for the Study of Liver Diseases.
FAU - Cai, Hongxia
AU  - Cai H
AD  - Department of Neurology, Tong-Ren Hospital, Shanghai Jiao Tong University School 
      of Medicine, Shanghai, China.
FAU - Cheng, Xing
AU  - Cheng X
AD  - State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell 
      Science, Institute of Biochemistry and Cell Biology, University of Chinese 
      Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Wang, Xiao-Ping
AU  - Wang XP
AUID- ORCID: 0000-0002-2936-5877
AD  - Department of Neurology, Tong-Ren Hospital, Shanghai Jiao Tong University School 
      of Medicine, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220413
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 789U1901C5 (Copper)
RN  - EC 7.2.2.8 (Copper-Transporting ATPases)
SB  - IM
MH  - Animals
MH  - Copper/metabolism
MH  - Copper-Transporting ATPases/genetics/metabolism
MH  - Disease Models, Animal
MH  - Genetic Therapy
MH  - Green Fluorescent Proteins/genetics/metabolism
MH  - *Hematopoietic Stem Cell Transplantation
MH  - Hepatocytes/metabolism
MH  - *Hepatolenticular Degeneration/genetics/metabolism/therapy
MH  - Mutation
PMC - PMC9790736
COIS- Nothing to report.
EDAT- 2022/03/28 06:00
MHDA- 2022/09/23 06:00
PMCR- 2022/12/25
CRDT- 2022/03/27 20:28
PHST- 2022/03/07 00:00 [revised]
PHST- 2021/12/29 00:00 [received]
PHST- 2022/03/25 00:00 [accepted]
PHST- 2022/03/28 06:00 [pubmed]
PHST- 2022/09/23 06:00 [medline]
PHST- 2022/03/27 20:28 [entrez]
PHST- 2022/12/25 00:00 [pmc-release]
AID - HEP32484 [pii]
AID - 10.1002/hep.32484 [doi]
PST - ppublish
SO  - Hepatology. 2022 Oct;76(4):1046-1057. doi: 10.1002/hep.32484. Epub 2022 Apr 13.