Cell Stem Cell: A protein partner that can heal the heart muscle

Scientists at the University of North Carolina School of Medicine have made significant progress in the promising field of cell reprogramming and organ regeneration, a discovery that could play an important role
in drugs that treat damaged hearts in the future.

In a study published in the journal, scientists at the University of North Carolina at Chapel Hill found a leaner and more efficient way to reprogram scar tissue cells (fibroblasts) into healthy cardiomyocytes (cardiomyocytes
).
Fibroblasts produce fibrous, stiff tissue that leads to heart failure after a heart attack or heart attack
.
Turning fibroblasts into cardiomyocytes is a potential future treatment strategy that could even one day cure this common deadly disease
.

Surprisingly, the key to the new cardiomyocyte-making technology turned out to be a gene activity control protein called Ascl1, a key protein
that turns fibroblasts into neurons.
Researchers had thought that Ascl1 was neuron-specific
.

"This is a groundbreaking finding, and we hope it will be useful for developing future heart therapy and potentially other types of therapeutic cell reprogramming," said Li Qian, the study's senior author, Dr.
Li Qian, an associate professor in the Department of Pathology and Laboratory Medicine at the University of North Carolina and associate director
of the McAllister Heart Institute at the University of North Carolina School of Medicine.

Over the past 15 years, scientists have developed various techniques to reprogram adult cells into stem cells, which are then induced to become other types of adult cells
.
More recently, scientists have been looking for ways to do this reprogramming more directly—moving directly from one mature cell type to another
.
It has been hoped that when these methods are as safe, effective and efficient as possible, doctors will be able to reprogram harmful cells in the patient's body into beneficial cells
with a simple injection method.

"Reprogramming fibroblasts has always been one of the important goals in this field," Qian said
.
"Fibroblast overactivity is the basis of many major diseases and conditions, including heart failure, chronic obstructive pulmonary disease, liver disease, kidney disease, and scarred brain damage
that occurs after stroke.
"

In the new study, Qian's team, including co-first author and postdoctoral researcher Haofei Wang, Ph.
D.
, and M.
D.
/PhD student Benjamin Keepers, used three existing techniques to reprogram mouse fibroblasts into cardiomyocytes, liver cells, and neurons
.
Their aim was to classify and compare
changes in gene activity patterns and gene activity regulators during these three different reprogramming processes.

Unexpectedly, the researchers found that fibroblasts reprogramming neurons activated a set of cardiomyocyte genes
.
Soon, they determined that this activation was caused by Ascl1, one of
the master-programmed "transcription factor" proteins used to make neurons.

Because Ascl1 activates the cardiomyocyte gene, the researchers added it to the tri-transcription factor mixture used to make cardiomyocytes to see what
happens.
They were surprised to find that it greatly improved the efficiency of reprogramming — the percentage of cells that successfully reprogrammed — by more than ten times
.
In fact, they found that they could now remove two of the three factors from the original cocktail, keeping only Ascl1 and another transcription factor
called Mef2c.

In further experiments, they found evidence that Ascl1 activates neurons and cardiomyocyte genes alone, but when accompanied by Mef2c, it deviates from the role of
pre-neurons.
In synergy with Mef2c, Ascl1 activates a series of cardiomyocyte genes
.

"Ascl1 and Mef2c work together to promote cardiomyocytes, which are roles that neither factor can play alone, forming an effective reprogramming cocktail," Qian said
.

The results showed that the primary transcription factors used for direct cell reprogramming were not necessarily specific to one cell type of
interest.

Perhaps more importantly, they represent another step
in the future of cell reprogramming therapies for major diseases.
The research team hopes to make a two-in-one synthetic protein that contains effective parts of Ascl1 and Mef2c and can be injected into a failing heart to repair them
.