Researchers from Niigata University , the University of Tokyo, Osaka
University and Tokyo Medical University, Japan have developed a new approach
that could revolutionize the treatment, prevention, and possibly reversal of
the damages caused by liver diseases. This novel strategy exploits small
extracellular vesicles (sEVs) derived from interferon-γ (IFN-γ)
pre-conditioned MSCs (γ-sEVs).
Cirrhosis and other chronic liver diseases remain a global health concern,
with close to 2 million deaths reported annually, these account for
approximately 3.5% of annual worldwide deaths. All these statistics are
largely driven by the fact that 75 million of the 2 billion people who
consume alcohol worldwide are diagnosed with alcohol-use disorders and are
at risk of developing alcohol- induced liver disease. In addition, the high
prevalence of viral hepatitis-induced liver damage continues to be on the
rise.
These sobering numbers inspired a team of scientists led by Prof. Shuji
Terai of the Division of Gastroenterology and Hepatology, Graduate School of
Medical and Dental Sciences, Niigata University, to build upon previous
knowledge that the ability to control fibrosis--which is the development of
fibrous connective tissue as a reparative response to injury or damage--in
livers under advanced cirrhosis, is often lost. In an interview Prof. Terai
said, "Our results showed that modified extracellular vesicles can become a
new therapeutic strategy for liver cirrhosis"
Since clinically advanced cirrhosis is an end-stage disease that can
effectively be treated only by liver transplantation at present, there is a
race in the field with many scientists developing targeted therapies for
modulating fibrosis and aiding tissue regeneration.
One of the most popular approaches is cell therapy, where mesenchymal
stromal cells (MSCs) and macrophages have shown potential towards inducing
liver fibrosis regression. The popularity of this approach is centered on
its cost-effectiveness; because MSCs are not only obtainable from the bone
marrow, but also from medical waste that include umbilical cord tissue,
adipose tissue, and dental pulp. Apart from the ease of availability, MSCs
can also be grown relatively easily in the lab. Furthermore, rather than
acting directly by replacing the damaged tissues, MSCs have previously been
shown to be medical signaling cells that indirectly produce cytokines,
chemokines, growth factors, and exosomes that are crucial for repairing and
regenerating damaged tissue. Over the years, considerable progress has been
made towards capacity building for research and clinical trials for novel
treatment strategies against liver diseases. This is exemplified by previous
demonstrations that MSCs have anti-inflammatory, anti-fibrotic, and
anti-oxidative effects through these humoral factors. Despite tissue
rejection being one of the barriers to cell/tissue transplantation
interventions; MSCs are attractive for possessing low immunogenicity, and
this can facilitate their use for both autologous (same individual) and
allogeneic (different individuals of the same species) transplantation, as
evidenced by applications in nearly 1000 clinical trials involving other
fields, including the treatment of liver diseases.
In a series of experimental mice studies, this team of researchers, from
Niigata University , the University of Tokyo, Osaka University and Tokyo
Medical University, Japan may have discovered that IFN-γ pre-conditioned
human AD-MSC-derived sEVs (AD-MSC-γ-sEVs) can induce anti-inflammatory
macrophage counts, which are the key players in tissue repair, including the
regression of fibrosis and promotion of tissue regeneration in vitro.
They report that both human adipose tissue-derived MSCs (AD-MSC-sEVs) and
AD-MSC-γ-sEVs can promote macrophage motility and phagocytic activity. In
addition, they also show that AD-MSC-γ- sEVs contain anti-inflammatory
macrophage inducible proteins and can effectively control inflammation and
fibrosis in a mouse model of cirrhosis. Following single-cell RNA-seq
application, they confirmed AD-MSC-γ-sEVs therapy can induce
multidimensional transcriptional changes. Taken together, these results
suggest that AD-MSC-derived sEVs can affect the shape and function of
macrophages and effectively recruit them into damaged areas, thereby
promoting damaged liver tissue repair.
In an interview, Dr. Atsunori Tsuchiya of the Division of Gastroenterology
and Hepatology, Graduate School of Medical and Dental Sciences, Niigata
University, who was part of the research team said, "Both mesenchymal
stromal cells and macrophages are reported to have therapeutic effects for
liver cirrhosis, however relationship of both cells and mechanisms of action
was not clear. We challenged this problem". He went on to add, "We found the
important fact that extracellular vesicles from interferon-γ can induce the
tissue repair macrophages, which can regress fibrosis and promote liver
regeneration effectively". These words were also echoed by Dr. Suguru
Takeuchi of the Division of Gastroenterology and Hepatology, Graduate School
of Medical and Dental Sciences, Niigata University, who was also part of the
research team, "In our previous study, we reported that intravenous
administration of mesenchymal stromal cells migrated to the lung, can work
as "conducting cells" and affect to macrophages " working cells" in the
liver." "In this study we first elucidated that extracellular vesicles from
mesenchymal stromal cells are key molecules to affect the macrophages",
added Dr. Takeuchi.
This proof-of-concept pilot study that complements macrophage therapy, holds
potential as a strategy for treating liver diseases using IFN-γ
pre-conditioned sEVs. However, further development and determination of the
mechanisms underlying Treg cell count induction by IFN-γ pre-conditioned
MSCs and sEVs still form part of their future research plans before these
findings can be translated to humans in phased and controlled clinical
trials.
Reference:
Small extracellular vesicles derived from interferon-γ pre-conditioned
mesenchymal stromal cells effectively treat liver fibrosis" was published in
npj Regenerative Medicine at DOI:
10.1038/s41536-021-00132-4