Abstract
Chronic liver damage leads to the onset of fibrogenesis. Rodent models for liver fibrosis have been widely used, but are less suitable for screening purposes. Therefore the aim of our study was to design a novel model for liver fibrosis in zebrafish embryos, suitable for high throughput screening. Furthermore, we evaluated the efficacy of mesenchymal stromal cells (MSCs) to inhibit the fibrotic process and thereby the applicability of this model to evaluate therapeutic responses. Zebrafish embryos were exposed to TAA or CCL4 and mRNA levels of fibrosis-related genes (Collagen-1α1, Hand-2, and Acta-2) and tissue damage-related genes (TGF-β and SDF-1a, SDF-1b) were determined, while Sirius-red staining was used to estimate collagen deposition. Three days after start of TAA exposure, MSCs were injected after which the fibrotic response was determined. In contrast to CCL4, TAA resulted in an upregulation of the fibrosis-related genes, increased extracellular matrix deposition and decreased liver sizes suggesting the onset of fibrosis. The applicability of this model to evaluate therapeutic responses was shown by local treatment with MSCs which resulted in decreased expression of the fibrosis-related RNA markers. In conclusion, TAA induces liver fibrosis in zebrafish embryos, thereby providing a promising model for future mechanistic and therapeutic studies.
Highlights
The liver is a vital organ with distinct functions like detoxification, metabolism and immune defence
Our current study shows that zebrafish embryos can be used as a robust and reliable novel model system for liver fibrosis
We found that 0.06% TAA treatment induced liver fibrosis, characterised by increased RNA expression of collagen, Hand-2 and Acta-2, smaller liver sizes and collagen deposition
Summary
The liver is a vital organ with distinct functions like detoxification, metabolism and immune defence. These include in vivo mouse and rat models, mostly based on the well-known carbon tetrachloride (CCL4) or thioacetamide (TAA) induced liver fibrosis Both compounds are metabolised by the hepatocytes into hepatotoxic metabolites leading to apoptosis of these cells and subsequently activation and proliferation of stellate cells[4,5]. In relation to liver fibrosis several animal studies already showed that MSCs can inhibit and reverse the fibrotic process[24,25,29,30] Supposed mechanisms for this effect include improvement of hepatocyte survival, inhibition of stellate cell activation, and proliferation and silencing of myofibroblasts[24,25,29,31,32]. We established a new high throughput zebrafish embryo model for liver fibrosis and evaluated its applicability to test potential new therapeutics by testing the ability of injected MSCs and fibroblasts to reduce the induction of liver fibrosis
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