Extracellular vesicles (EVs) are nano-sized, lipid bilayer-delimited particles that are released by our cells and deliver important materials to other cells to aid cellular communication. Now, a study in mice led by WEHI and La Trobe University has found EVs could potentially be used to better detect the level of tissue damage in our bodies. The new study revealed, for the first time, a link between levels of EVs in the blood and tissue damage caused by blood cancers and other diseases such as leukemia.
The findings are published in Nature Communications in an article titled, “In situ visualization of endothelial cell-derived extracellular vesicle formation in steady state and malignant conditions.”
“Endothelial cells are integral components of all vasculature within complex organisms. As they line the blood vessel wall, endothelial cells are constantly exposed to a variety of molecular factors and shear force that can induce cellular damage and stress,” the researchers wrote. “However, how endothelial cells are removed or eliminate unwanted cellular contents, remains unclear. The generation of large extracellular vesicles (EVs) has emerged as a key mechanism for the removal of cellular waste from cells that are dying or stressed. Here, we used intravital microscopy of the bone marrow to directly measure the kinetics of EV formation from endothelial cells in vivo under homeostatic and malignant conditions. These large EVs are mitochondria-rich, expose the ‘eat me’ signal phosphatidylserine, and can interact with immune cell populations as a potential clearance mechanism.”
The findings in mice suggest monitoring the levels of EVs in the blood could provide direct insight into the level of tissue damage, critical information that may inform ways to better detect and treat diseases.
Research into how EVs form and their link to disease progression is challenging because of their small size, with most studies restricted to a “cells-in-a-dish” approach. However, the researchers were able to overcome this barrier by imaging live EVs inside the bone marrow of mice.
First author and WEHI cell biologist, Georgia Atkin-Smith, PhD, said the team used high-resolution microscopy that can see directly inside the bone marrow of live organisms to capture the formation of EVs from blood vessels.
“No other study in the world has been able to achieve this so it’s a huge win for Australia’s scientific community,” Atkin-Smith said.
“In this study, we’ve shown that the development of leukemia can degrade healthy blood vessels in the bone marrow. Mice with extensive blood vessel damage in their bone marrow had elevated levels of EVs in their blood, while healthy mice did not.”
“This revealed—for the first time—that there is a link between EVs in the blood and tissue damage during cancer.”
The potential link between EVs and blood vessel damage was first hypothesized in 2018 by senior author and WEHI Laboratory head, associate professor Edwin Hawkins, PhD, who is an expert in in vivo imaging.
“To have seen how the process of EV formation occurs with our own eyes after four years of research was an incredible moment,” Atkin-Smith said.
“Pictures tell a thousand words, and these ones have significantly advanced our understanding into EVs by showing how they form under both healthy settings and during disease. This has not only developed a new framework to study the formation of EVs in model organisms, but could inform new diagnostic tools to monitor the level of tissue damage observed during disease through a simple blood test. It’s an incredibly exciting advancement.”
The study involved a significant collaboration with Ivan Poon, PhD, professor and director of the La Trobe Research Center for Extracellular Vesicles (RCEV). The study also involved collaborations with the University of Melbourne, the Florey, the Olivia Newton-John Cancer Research Institute, the Peter MacCallum Cancer Centre (Peter Mac), and Monash University.
La Trobe PhD candidate and second author, Jascinta Santavanond, has been developing imaging techniques to study cell death and zebrafish biology. “This study is a testament to what can be achieved through scientific collaboration,” she said.
“By working together, we have validated our results in fish, mice, and human samples, truly highlighting the impact of the research.”
The WEHI research team is now assessing whether EVs can be used as a biomarker in acute myeloid leukemia (AML) patients, through a collaboration with Peter Mac. They hope to develop new tools and techniques that would allow clinicians to determine the impact of disease on healthy tissue, and assess the disease progression by analyzing patient samples.