Johns Hopkins 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 the June 5 online edition of journal
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 labs. 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.”
Along with Levchenko and Kshitiz, the co-authors of the
study were Eun Hyun Ahn and Deok-Ho Kim, both of the University of Washington
and formerly of Johns Hopkins, and the following Johns Hopkins researchers:
Maimon E. Hubbi, John Downey, Junaid Afzal, Sergio Rey, Connie Chang, Arnab
Kundu, Gregg L. Semenza, and Roselle M. Abraham.
Funding for the research was provided by the National
Institutes of Health, the American Heart Association and the American Asthma
Foundation and other sources.
The findings are protected in part by a provisional patent
filed through the Johns Hopkins
Technology Transfer office.
Related links:
Andre Levchenko’s Lab Page: https://jshare.johnshopkins.edu/alevche1/web/
Johns Hopkins Department of Biomedical Engineering: www.bme.jhu.edu
Johns Hopkins Institute for Cell Engineering: http://www.hopkins-ice.org/
