On August 10th 2024, the team led by Dong Wang from the Institute for Translational Medicine published a research paper titled “Two-dimensional vascularized liver organoid on extracellular matrix with defined stiffness for modeling fibrotic and normal tissues” (doi: 10.1177/20417314241268344) in the Journal of Tissue Engineering (Q1). They successfully constructed a novel two-dimensional vascularized liver organoid model that can simulate different stiffness microenvironments of fibrotic and normal tissues. This model can not only be used to evaluate the anti-fibrotic effects of candidate drugs but also simultaneously examine their potential side effects on normal tissues, providing a new platform tool for anti-fibrotic drug screening. Lei Ma, a 2021 Master student from the Institute for Translational Medicine and School of Basic Medicine, is the first author. This research was supported by the National Natural Science Foundation of China, the Shandong Provincial Natural Science Foundation Joint Fund for Tumor Prevention and Control, the Shandong Provincial Natural Science Foundation, the Qingdao Natural Science Foundation, and the Qingdao University “Medicine+” Discipline Cluster Joint Exploration Project.
To validate the model, the authors evaluated two inhibitors of the TGFβ signaling pathway: A83-01 and Pirfenidone (PFD), with the latter already FDA-approved for clinical treatment of pulmonary fibrosis. The study found that A83-01 can effectively inhibit fibrosis but has some inhibitory effects on the microvasculature of normal tissues, indicating potential side effects. Pirfenidone, on the other hand, had less impact on gene expression in normal tissues, suggesting potentially fewer side effects. Although Pirfenidone’s inhibitory effect on fibrotic gene expression was not as strong as A83-01, it could still specifically inhibit collagen (Col1a1 and Col3a1) expression. Given that collagen is the end product of fibrotic tissue, this result indicates that Pirfenidone has a certain anti-fibrotic effect. These research findings are consistent with clinical trial results.
Fibrosis is a widespread disease that can occur in almost all human organs, leading to organ dysfunction and even failure. Liver fibrosis often progresses to cirrhosis, ultimately leading to liver cancer. Typical characteristics of fibrotic tissue include microvascular degeneration and tissue hardening due to extensive collagen protein deposition. Studying the regulatory mechanisms of microvasculature during fibrosis has important clinical translational significance. Due to physiological, pathological, and genetic differences between animals and humans, many candidate drugs that succeed in animal studies fail in clinical trials. Therefore, establishing in vitro microvascular models has important translational medical significance.
Dong Wang’s research group has been investigating microvessels for many years. They focus on translational medical research in recent years. In 2022, the group published a new adult microvascular model in the Journal of Tissue Engineering (Q1) (doi: 10.1177/20417314221125310). Building on this, the group subsequently published another paper in ATVB (Q1) (doi: 10.1161/ATVBAHA.123.319119), a classic journal in the vascular field, in 2023, revealing a new mechanism by which the extracellular matrix regulates pericyte differentiation into myofibroblasts through mechanical stimulation of microvascular endothelial cells, causing them to secrete pro-fibrotic factors.
Original link: https://doi.org/10.1177/20417314241268344.
