Cellular regeneration therapy restores damaged liver tissue faster than
ever
Scientists improve liver regeneration in mice, which could lead to new treatments for liver disease
Date:
April 26, 2022
Source:
Salk Institute
Summary:
Mammals can't typically regenerate organs as efficiently as
other vertebrates, such as fish and lizards. Now, scientists
have found a way to partially reset liver cells to more youthful
states -- allowing them to heal damaged tissue at a faster rate
than previously observed. The results reveal that the use of
reprogramming molecules can improve cell growth, leading to better
liver tissue regeneration in mice.
FULL STORY ========================================================================== Mammals can't typically regenerate organs as efficiently as other
vertebrates, such as fish and lizards. Now, Salk scientists have found
a way to partially reset liver cells to more youthful states -- allowing
them to heal damaged tissue at a faster rate than previously observed. The results, published in Cell ReportsonApril 26, 2022, reveal that the use
of reprogramming molecules can improve cell growth, leading to better
liver tissue regeneration in mice.
==========================================================================
"We are excited to make strides at repairing cells of damaged livers
because, someday, approaches like this could be extended to replacing
the whole organ itself," says corresponding author Juan Carlos Izpisua Belmonte, a professor in Salk's Gene Expression Laboratory and holder of
the Roger Guillemin Chair. "Our findings could lead to the development
of new therapies for infection, cancer and genetic liver diseases as
well as metabolic diseases like nonalcoholic steatohepatitis (NASH)."
The authors previously showed how four cellular reprogramming molecules
-- Oct- 3/4, Sox2, Klf4 and c-Myc, also called "Yamanaka factors" -- can
slow down the aging process as well as improve muscle tissue regeneration capacity in mice.
In their latest study, the authors used Yamanaka factors to see if they
could increase liver size and improve liver function while extending
the health span of the mice. The process involves partially converting
mature liver cells back to "younger" states, which promotes cell growth.
"Unlike most of our other organs, the liver is more effective at repairing damaged tissue," says co-first author Mako Yamamoto, a staff researcher in
the Izpisua Belmonte lab. "To find out if mammalian tissue regeneration
could be enhanced, we tested the efficacy of Yamanaka factors in a mouse
liver model." The issue many researchers in the field face is how to
control the expression of factors needed for improving cell function and rejuvenation as some of these molecules can cause rampant cell growth,
such as occurs in cancer. To circumvent this, Izpisua Belmonte's team used
a short-term Yamanaka factor protocol, where the mice had their treatment administered for only one day. The team then tracked the activity of the partially reprogrammed liver cells by taking periodic samples and closely monitoring how cells divided over several generations. Even after nine
months -- roughly a third of the animal's life span -- none of the mice
had tumors.
"Yamanaka factors are truly a double-edged sword," says co-first author
Tomoaki Hishida, a former postdoctoral fellow in the Izpisua Belmonte
lab and current associate professor at Wakayama Medical University
in Japan. "On the one hand, they have the potential to enhance liver regeneration in damaged tissue, but the downside is that they can cause
tumors. We were excited to find that our short-term induction protocol has
the good effects without the bad -- improved regeneration and no cancer."
The scientists made a second discovery while studying this reprogramming mechanism in a lab dish: A gene called Top2ais involved in liver cell reprogramming and is highly active one day after short-term Yamanaka
factor treatment. Top2a encodes Topoisomerase 2a, an enzyme that helps
break up and rejoin DNA strands. When the researchers blocked the gene,
which lowered Topoisomerase 2a levels, they saw a 40-fold reduction in
cellular reprogramming rates, leading to far fewer young cells. The exact
role that Top2a plays in this process remains a future area of research.
"There is still much work to be done before we can fully understand the molecular basis underlying cellular rejuvenation programming approaches,"
says Izpisua Belmonte. "This is a necessary requirement for developing effective and universal medical treatments and reversing the effects
of human disease." Izpisua Belmonte is currently Institute Director of
Altos Labs Inc., in addition to being a professor at the Salk Institute.
This work was supported by a Uehara Memorial Foundation research
fellowship UCAM and Fundacion Dr. Pedro Guillen.
========================================================================== Story Source: Materials provided by Salk_Institute. Note: Content may
be edited for style and length.
========================================================================== Journal Reference:
1. Tomoaki Hishida, Mako Yamamoto, Yuriko Hishida-Nozaki, Changwei
Shao,
Ling Huang, Chao Wang, Kensaku Shojima, Yuan Xue, Yuqing Hang, Maxim
Shokhirev, Sebastian Memczak, Sanjeeb Kumar Sahu, Fumiyuki Hatanaka,
Ruben Rabadan Ros, Matthew B. Maxwell, Jasmine Chavez, Yanjiao Shao,
Hsin-Kai Liao, Paloma Martinez-Redondo, Isabel Guillen-Guillen,
Reyna Hernandez-Benitez, Concepcion Rodriguez Esteban, Jing Qu,
Michael C.
Holmes, Fei Yi, Raymond D. Hickey, Pedro Guillen Garcia, Estrella
Nun~ez Delicado, Antoni Castells, Josep M. Campistol, Yang Yu,
Diana C.
Hargreaves, Akihiro Asai, Pradeep Reddy, Guang-Hui Liu, Juan Carlos
Izpisua Belmonte. In vivo partial cellular reprogramming enhances
liver plasticity and regeneration. Cell Reports, 2022; 39 (4):
110730 DOI: 10.1016/j.celrep.2022.110730 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220426153653.htm
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