Postdoctoral Fellow The University of Hong Kong Hong Kong, Hong Kong
Abstract: Liver fibrosis (LF) results from the excessive accumulation of fibrous connective tissue due to chronic liver inflammation. As LF advances, it can lead to deathly conditions such as cirrhosis and hepatocellular carcinoma (HCC). Currently, no FDA-approved drugs specifically target LF, leaving liver transplantation as the only option in advanced cases—a procedure fraught with limited donor availability. This highlights the critical need for innovative therapies to prevent LF from advancing to cirrhosis or HCC. Extracellular vesicles (EVs), particularly those originating from mesenchymal stem cells (MSC-EVs), hold significant potential as tools for regenerative medicine. In our previous research, we developed a novel MSC-EV system designed to target non-phagocytic cells, specifically hepatic stellate cells (HSCs)—the primary drivers of LF. This work, published in Nature Nanotechnology, demonstrated the creation of an albumin sponge on the EV surface, which enhanced MSC-EVs’ targeting capabilities toward HSCs and hepatocytes. This breakthrough opened new avenues for refining EV systems to improve their targeting efficiency and therapeutic applicability.
Building on this foundation, our current study aims to enrich EVs with antifibrotic cargo while optimizing the albumin sponge layer. To achieve this, we employ a Design of Experiments approach, allowing simultaneous evaluation of multiple optimizable factors at varying levels. These factors include hypoxic conditions with different oxygen levels, albumin types and concentrations, and incubation durations.
This model enables the identification of optimal culturing parameters to produce EVs with a refined albumin layer, confirmed by measuring albumin content and evaluating in vivo cellular uptake in liver subpopulations. These EVs also exhibit potent anti-inflammatory effects, demonstrated by their impact on LPS-treated macrophages, and antifibrotic properties through the suppression of HSC activation in vitro.
Future efforts will focus on validating these EVs' therapeutic activities in vivo and unraveling their mechanisms of action. This will involve analyzing their transcriptomic and proteomic signatures, leveraging bioinformatics tools, and investigating intracellular trafficking to identify potential molecular targets.
