Previous liver regeneration induces fibro-protective mechanisms during thioacetamide-induced chronic liver injury

Document Type

Journal Article

Publication Title

The International Journal of Biochemistry & Cell Biology



PubMed ID





School of Medical and Health Sciences




National Health and Medical Research Council

Grant Number

NHMRC Number: APP1087125


Gratte, F. D., Pasic, S., Abu Bakar, N. D. B., Gogoi-Tiwari, J., Liu, X., Carlessi, R., ... Tirnitz-Parker, J. E. E. (2021). Previous liver regeneration induces fibro-protective mechanisms during thioacetamide-induced chronic liver injury. The International Journal of Biochemistry & Cell Biology, 134, article 105933. https://doi.org/10.1016/j.biocel.2021.105933


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 naïve 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 naïve 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.



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