Cell Stem Cell, a "nerve-specific" protein that can heal the heart

Human fibroblasts are reprogrammed into cardiomyocytes
.
Immunofluorescence shows different molecules: DNA (blue), cardiac troponin T (orange), and α actin (green).

According to research led by Dr.
Li Qian of the University of North Carolina School of Medicine, a protein that helps neurons develop also has the function
of reprogramming scar tissue cells into cardiomyocytes.

Researchers at the University of North Carolina School of Medicine have made important advances in exciting areas such as cell reprogramming and organ regeneration, and their findings could have a significant impact
on future developments in the treatment of heart injury.

Researchers at the University of North Carolina at Chapel Hill found a leaner, more efficient way to recombine fibroblasts that make up scar tissue into healthy cardiomyocytes
in a recent study published in the journal Cell Stem Cell.
Fibroblasts are responsible for fibrous, stiff tissue that leads to heart failure
after a heart attack or heart attack.
Converting fibroblasts into cardiomyocytes is a possible future treatment that could even cure this widespread and deadly disease
.
Surprisingly, the key to the new method of making cardiomyocytes turned out to be Ascl1, a protein that controls gene activity and is known to play an important role
in the transformation of fibroblasts into neurons.
Ascl1 was previously thought to be neuron-specific
.

"This is a groundbreaking discovery, and we hope it will be useful for developing future cardiac therapies and potentially other types of therapeutic cell reprogramming," said Li Qian, Ph.
D.
, senior author of the study, 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 and then induce those stem cells to become other types of adult cells
.
Recently, scientists have been looking for ways to do this reprogramming more directly—directly from one mature cell type to another
.
It has been hoped that when these methods reach maximum safety, effectiveness and efficiency, doctors will be able to reprogram harmful cells in the patient's body into beneficial cells
with a simple injection.

"Reprogramming fibroblasts has been one of the important targets in the field," Qian said
.
"Hyperactive fibroblasts underlie many major diseases and conditions, including heart failure, chronic obstructive pulmonary disease, liver disease, kidney disease, and scar-like brain injury
that occurs after stroke.
"

In the new study, including co-first author Haofei Wang, 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 cellular gene activity patterns and gene activity regulators during these three different reprogramming processes.

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

Because Ascl1 activates the heart muscle cell gene, the researchers added it to a mixture of three transcription factors used to make heart muscle cells to see what happens
.
They were surprised to find that it dramatically increased the efficiency of reprogramming—the proportion of cells that successfully reprogrammed it—by more than tenfold
.
In fact, they found that they could now remove two of the three factors in the original cocktail, keeping only Ascl1 and another transcription factor
called Mef2c.

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

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

The results show that the main transcription factors used for direct cell reprogramming are not necessarily specific to one cell type
of interest.

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

Cross-lineage potential of Ascl1 uncovered by comparing diverse reprogramming regulatomes