UNC School of Medicine scientists overcame a
significant barrier to convert scar-making fibroblasts into living, beating
cardiomyocytes
.
Newswise, March 18, 2016--Patients with heart failure often
have a buildup of scar tissue that leads to a gradual loss of heart function.
In a new study published today in the journal Cell Stem Cell,
researchers from the University of North Carolina School of Medicine report
significant progress toward a novel approach that could shrink the amount of
heart scar tissue while replenishing the supply of healthy heart muscle.
“Our past work brought hope that we could one day improve
heart function in people with heart failure by converting scar tissue into
beating heart muscle,” said Li Qian, PhD, assistant professor of pathology and
laboratory medicine and the study’s senior author.
“But that was more of a proof-of-principle study, and the
conversion rate was quite low. Now we have found the barrier to conversion, and
by removing it, we have been able to significantly increase the yield of
muscle-like cells.”
Heart failure has no cure and currently affects an estimated
5.7 million people in the United States. Common symptoms include shortness of
breath, fatigue, and swelling, all of which often worsen as the heart weakens
over time.
“Our hope is that this approach could extend the lives of
people with heart failure and markedly improve their quality of life in the
future,” said Qian, who is also a member of the McAllister Heart Institute at
UNC.
In 2012, Qian and her colleagues created a “cocktail” of
proteins capable of converting fibroblasts, which create scar tissue, into
cardiomyocytes – heart muscle cells that beat on their own exactly the way
regular heart muscle cells do.
Notably, the team’s approach did not require converting
fibroblasts into stem cells, which is typical of other tissue regeneration
techniques. Qian’s approach lowered the likelihood of uncontrolled cell growth
and tumor formation.
In experiments using mice, the cocktail proved successful at
shrinking the size of scar tissue and improving heart function. But the process
had remained disappointingly slow – until now.
“We wanted to have a better yield and shorten the conversion
time so in the future this process could be fast, easy, and efficient for
disease modeling or for treatment,” Qian said.
The new breakthrough came when the team discovered that a gene
called Bmi1 interfered with the expression of other key genes needed to convert
fibroblasts into heart muscle cells. Bmi1 previously had been investigated for
its role in neural stem cells and cancer cells, but this is the first study to
pinpoint a role in its interaction with cardiogenic genes.
When the team depleted Bmi1, the conversion rate sped up
markedly; the percentage of fibroblasts that transformed into heart muscle
cells increased 10-fold. Repressing Bmi1 also allowed Qian’s team to simplify
the cocktail by reducing the number of different proteins in it.
The ultimate goal, Qian said, is to refine the cocktail into a
pill that could safely be given to patients during a heart attack or after the
heart has already become damaged, thus reducing the long-term loss of
functional heart tissue and helping people live longer, healthier lives. If
further experiments using larger animal models bear out, Qian estimates such a
pill could be developed within a decade.
The technique also holds potential for improving personalized
medicine. Currently, there are a number of therapeutics doctors can prescribe
to help improve a patient’s heart function, but there is often trial and error
involved to find the most effective drug with the fewest side effects. Qian’s
protein cocktail could help avoid this.
For instance, if Qian’s technique could convert a patient’s
skin cells into heart muscle cells in a lab dish, then lab technicians could
use the resulting cell culture to quickly screen existing drugs and find the
one most likely to help a specific patient.
In addition, the team’s approach and platform built to study
barriers to cardiac reprogramming could help to increase yields for studies
focused on reprogramming other cells, such as neurons, pancreas cells, and
liver cells for regenerative purposes.
“Hopefully these findings and our approach can be leveraged so
that other researchers can identify the barriers to regenerating other types of
target tissues more efficiently,” Qian said.
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