PMID- 33540107 OWN - NLM STAT- MEDLINE DCOM- 20210928 LR - 20240404 IS - 1878-5875 (Electronic) IS - 1357-2725 (Linking) VI - 134 DP - 2021 May TI - Previous liver regeneration induces fibro-protective mechanisms during thioacetamide-induced chronic liver injury. PG - 105933 LID - S1357-2725(21)00017-0 [pii] LID - 10.1016/j.biocel.2021.105933 [doi] AB - Chronic liver injury is characterised by continuous or repeated epithelial cell loss and inflammation. Hepatic wound healing involves matrix deposition through activated hepatic stellate cells (HSCs) and the expansion of closely associated Ductular Reactions and liver progenitor cells (LPCs), which are thought to give rise to new epithelial cells. In this study, we used the murine thioacetamide (TAA) model to reliably mimic these injury and regeneration dynamics and assess the impact of a recovery phase on subsequent liver injury and fibrosis. Age-matched naive or 6-week TAA-treated/4-week recovered mice (C57BL/6 J, n = 5-9) were administered TAA for six weeks (C57BL/6 J, n = 5-9). Sera and liver tissues were harvested at key time points to assess liver injury biochemically, by real-time PCR for fibrotic mediators, Sirius Red staining and hydroxyproline assessment for collagen deposition as well as immunofluorescence for inflammatory, HSC and LPC markers. In addition, primary HSCs and the HSC cell line LX-2 were co-cultured with the well-characterised LPC line BMOL and analysed for potential changes in expression of fibrogenic mediators. Our data demonstrate that recovery from a previous TAA insult, with LPCs still present on day 0 of the second treatment, led to a reduced TAA-induced disease progression with less severe fibrosis than in naive TAA-treated animals. Importantly, primary activated HSCs significantly reduced pro-fibrogenic gene expression when co-cultured with LPCs. Taken together, previous TAA injury established a fibro-protective molecular and cellular microenvironment. Our proof-of principle HSC/LPC co-culture data demonstrate that LPCs communicate with HSCs to regulate fibrogenesis, highlighting a key role for LPCs as regulatory cells during chronic liver disease. CI - Copyright (c) 2021 Elsevier Ltd. All rights reserved. FAU - Gratte, Francis D AU - Gratte FD AD - School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia; Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Australia. Electronic address: 32707216@student.murdoch.edu.au. FAU - Pasic, Sara AU - Pasic S AD - Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Australia. Electronic address: sara.pasic@postgrad.curtin.edu.au. FAU - Abu Bakar, N Dianah B AU - Abu Bakar NDB AD - Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Australia. Electronic address: nurdianah.abubakar@postgrad.curtin.edu.au. FAU - Gogoi-Tiwari, Jully AU - Gogoi-Tiwari J AD - School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia; Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Australia. Electronic address: jully.gogoitiwari@murdoch.edu.au. FAU - Liu, Xiao AU - Liu X AD - Department of Surgery, University of California, San Diego, La Jolla, CA, USA. Electronic address: xil094@ucsd.edu. FAU - Carlessi, Rodrigo AU - Carlessi R AD - Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Australia. Electronic address: Rodrigo.Carlessi@curtin.edu.au. FAU - Kisseleva, Tatiana AU - Kisseleva T AD - Department of Surgery, University of California, San Diego, La Jolla, CA, USA. Electronic address: tkisseleva@health.ucsd.edu. FAU - Brenner, David A AU - Brenner DA AD - School of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: dbrenner@health.ucsd.edu. FAU - Ramm, Grant A AU - Ramm GA AD - QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; The University of Queensland, Brisbane, QLD, Australia. Electronic address: Grant.Ramm@qimrberghofer.edu.au. FAU - Olynyk, John K AU - Olynyk JK AD - Fiona Stanley and Fremantle Hospital Group, Perth, WA, Australia; School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia. Electronic address: John.Olynyk@health.wa.gov.au. FAU - Tirnitz-Parker, Janina E E AU - Tirnitz-Parker JEE AD - Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Australia. Electronic address: n.tirnitz-parker@curtin.edu.au. LA - eng GR - P50 AA011999/AA/NIAAA NIH HHS/United States GR - R01 DK099205/DK/NIDDK NIH HHS/United States GR - U01 AA029019/AA/NIAAA NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210201 PL - Netherlands TA - Int J Biochem Cell Biol JT - The international journal of biochemistry & cell biology JID - 9508482 RN - 075T165X8M (Thioacetamide) SB - IM MH - Animals MH - Cells, Cultured MH - Chemical and Drug Induced Liver Injury/etiology/metabolism/*pathology MH - Coculture Techniques MH - Disease Models, Animal MH - Hepatic Stellate Cells/*cytology/metabolism MH - Liver/*cytology/metabolism MH - Liver Cirrhosis/etiology/metabolism/*pathology MH - Liver Regeneration/*physiology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Stem Cells/*cytology/metabolism MH - Thioacetamide/*toxicity OTO - NOTNLM OT - Chronic liver disease OT - Fibrosis OT - Hepatic stellate cells OT - Liver progenitor cells OT - Thioacetamide EDAT- 2021/02/05 06:00 MHDA- 2021/09/29 06:00 CRDT- 2021/02/04 20:13 PHST- 2020/08/18 00:00 [received] PHST- 2021/01/20 00:00 [revised] PHST- 2021/01/20 00:00 [accepted] PHST- 2021/02/05 06:00 [pubmed] PHST- 2021/09/29 06:00 [medline] PHST- 2021/02/04 20:13 [entrez] AID - S1357-2725(21)00017-0 [pii] AID - 10.1016/j.biocel.2021.105933 [doi] PST - ppublish SO - Int J Biochem Cell Biol. 2021 May;134:105933. doi: 10.1016/j.biocel.2021.105933. Epub 2021 Feb 1.