Johns Hopkins University
researchers have discovered that a single protein molecule may hold the key to
turning cardiac stem cells into blood vessels or muscle tissue, a finding that
may lead to better ways to treat heart attack patients.
Human heart tissue does not heal well after a heart attack, instead forming
debilitating scars. However, for reasons not completely understood, stem cells
can assist in this repair process by turning into the cells that make up
healthy heart tissue, including heart muscle and blood vessels. Recently,
doctors elsewhere have reported promising early results in the use of cardiac
stem cells to curb the formation of unhealthy scar tissue after a heart attack.
But the discovery of a “master molecule” that guides the destiny of these stem
cells could result in even more effective treatments for heart patients, the
Johns Hopkins researchers say.
In a study published in Science Signaling, the team reported that
tinkering with a protein molecule called p190RhoGAP shaped the development of
cardiac stem cells, prodding them to become the building blocks for either
blood vessels or heart muscle. The team members said that by altering levels of
this protein, they were able to affect the future of these stem cells.
“In biology, finding a central regulator like this is like finding a pot of
gold,” said Andre Levchenko, a biomedical engineering professor and member of
the Johns Hopkins Institute for Cell Engineering, who supervised the research
effort.
The lead author of the journal article, Kshitiz, a postdoctoral fellow who
uses only his first name, said, “Our findings greatly enhance our understanding
of stem cell biology and suggest innovative new ways to control the behavior of
cardiac stem cells before and after they are transplanted into a patient. This
discovery could significantly change the way stem cell therapy is administered
in heart patients.”
Earlier this year, a medical team at Cedars-Sinai
Medical Center
in Los Angeles
reported initial success in reducing scar tissue in heart attack patients after
harvesting some of the patient’s own cardiac stem cells, growing more of these
cells in a lab and transfusing them back into the patient. Using the stem cells
from the patient’s own heart prevented the rejection problems that often occur
when tissue is transplanted from another person.
Levchenko’s team has been trying to figure out what, at the molecular level,
causes the stem cells to change into helpful heart tissue. If they could solve
this mystery, the researchers hoped the cardiac stem cell technique used by the
Los Angeles
doctors could be altered to yield even better results.
During their research, the Johns Hopkins team members wondered whether
changing the surface on which the harvested stem cells grew would affect the
cells’ development. The researchers were surprised to find that growing the
cells on a surface whose rigidity resembled that of heart tissue caused the
stem cells to grow faster and to form blood vessels. This cell population boom
had occurred far less often in the stem cells grown in the glass or plastic
dishes typically used in biology laboratories. This result also suggested why formation
of cardiac scar tissue, a structure with very different rigidity, can inhibit
stem cells naturally residing there from regenerating the heart.
Looking further into this stem cell differentiation, the Johns Hopkins
researchers found that the increased cell growth occurred when there was a
decrease in the presence of the protein p190RhoGAP. “It was the kind of master
regulator of this process,” Levchenko said. “And an even bigger surprise was
that if we directly forced this molecule to disappear, we no longer needed the
special heart-matched surfaces. When the master regulator was missing, the stem
cells started to form blood vessels, even on glass.”
A final surprise occurred when the team decided to increase the presence of p190RhoGAP,
instead of making it disappear. “The stem cells started to turn into cardiac
muscle tissue, instead of blood vessels,” Levchenko said. “This told us that
this amazing molecule was the master regulator not only of the blood vessel
development, but that it also determined whether cardiac muscles and blood
vessels would develop from the same cells, even though these types of tissue
are quite different.”
But would these lab discoveries make a difference in the treatment of living
beings? To find out, the researchers, working on the heart-matching surfaces
they had designed, limited the production of p190RhoGAP within the heart cells. The
cells that possessed less of this protein integrated more smoothly into an
animal’s blood vessel networks in the aftermath of a heart attack. In addition,
more of these transplanted heart cells survived, compared to what had occurred
in earlier cell-growing procedures.
Kshitiz said that the special heart-like surface on which the cardiac stem
cells were grown triggers regulation of the master molecule, which then steers
the next steps. “This single protein can control the cells’ shape, how fast
they divide, how they become blood vessel cells and how they start to form a
blood vessel network,” he said. “How it performed all of these myriad tasks
that require hundreds of other proteins to act in a complex interplay was an
interesting mystery to address, and one that rarely occurs in biology. It was
like a molecular symphony being played in time, with each beat placed right at
the moment before another melody has to start.”
Source: Johns Hopkins University
