Postdoctoral fellow The University of Hong Kong Hong Kong, Hong Kong
Abstract: Biliary atresia (BA) is a severe infantile biliary system disease characterized by the obstruction and damage of the bile ducts, resulting in cholestasis, which may cause the liver to deteriorate progressively and eventually lead to liver failure. There is a multifactorial cause of BA, while the precise pathogenesis is still unknown. Clinical research has been conducted to investigate environmental and host factors, including contamination toxins, virus infection, genetic mutation, and aberrant immune responses. The liver extracellular matrix (ECM) contains growth factors and bioactive molecules to regulate diverse cellular functions, which play a key role in liver development and disease diagnosis and treatment.
The Ross River virus (RRV)-induced animal BA model, mimicking most types of extrahepatic BA in children, is used for studying BA development and liver fibrosis processing. Mice infected with RRV were used to study the variation of ECM protein expression in BA and mimic liver fibrosis processing in humans. The symptoms of cholestasis appear between the fourth- and eleventh-day post-infection, and 14-day-old mice are used to mimic the state of BA in infants and understand fibrosis in this phase. A stark contrast is seen between the healthy control group and BA mice, with the latter showing yellow and dark surface livers with yellow spots.
WT and BA mouse livers were harvested for preparing ECM and ECM hydrogels. Both WT and BA liver ECM were analyzed using a proteomic method. 1768 protein segments were detected and identified, and 1080 of them are upregulated and 688 of them are downregulated. The top 10 upregulated and downregulated protein segments in BA were demonstrated. The C5/C5b a factor of the complement system was detected in the BA mouse and showed a higher expression compared to the controlled liver tissue sections. ECM was further digested to form WT and BA liver ECM-derived hydrogel for liver hepatobiliary progenitors-derived organoid culture. It is seen that some remaining ECM factors could inhibit organoid growth and proliferation. The liver ECM of mice with/without BA can be used to identify potential niche factors that impact disease initiation/progression of BA. The ECM derived from decellularized tissues can be used as a tissue engineering scaffold for tissue repair and regeneration.
Funding Source: The authors thank all the patients who participated in this study. This work is supported by Theme-based Research Scheme 2021 (T12-712/21-R); Health and Medical Research Fund (08192376).
