Stem Cell Research

Stem cells or progenitor cells needed for development of key blood vessels of the heart may not proliferate normally in some fetuses, according to a Medical College of Georgia researcher.
An inadequate number of cardiac neural crest stem cells can hinder the formation of an aorta to transport oxygen-rich blood to the body and pulmonary trunk to take de-oxygenated blood back to the lungs, according to Dr. Simon J. Conway, developmental biologist and geneticist, whose research won this year's Young Investigator Award from the International Society for Heart Research – American Section.
This heart defect, persistent truncus arteriosus, may contribute to up to 20 percent of spontaneous miscarriages and 10 percent of still births and cause significant mortality in babies who have a poorly beating heart in conjunction with the incompletely formed outflow tract.
In research scheduled to published this summer with an accompanying editorial in Cardiovascular Research, Dr. Conway used a mouse model to trace in early fetal development the steps of normal septation or formation of the two vessels.
Researchers found a problem occurred very early in development, before the heart began to form, as neural crest stem cells prepared to leave the neural tube – a starting point for cells that will eventually form key structures such as the spinal cord, brain and heart.
"The neural crest stem cells give rise to all those cells that will leave the neural tube, populate the heart and give rise to the septum between the two vessels," Dr. Conway said. "At the very early stage, not enough of them are specified, so there are insufficient stem cells. You start off with a fairly limited number that have to multiply 10 or 20 or 30 times so they have enough cells to migrate to the heart and give rise to the septum," he said.
Dr. Conway's previous studies, published in 1997 in the journal Development, showed that cardiac neural crest cells never arrived in the heart and pointed him toward the current study to determine why not.
"Cells have to leave the neural tube, migrate through tissue, find their way to the outflow track of the heart, then give rise to the septum," he said. "We have been able to show in the past that they don't arrive in the heart. So the ‘black box' was what happened between the neural tube and the heart."
What he found in his mouse model – called the Splotch (SP2H) because of the white splotch on its belly – was that the stem cells that would ultimately develop the outflow tract septum of the heart didn't expand normally and didn't proliferate; there simply weren't enough of them to do the job.
Now he's taking the research back one more step in time to find why there aren't enough stem cells. "We are working out what is controlling the development and formation of these neural crest stem cells to see if we can determine the primary cause that gives rise to their deficiency and ultimately the heart defect. If there is a way we can artificially give rise to more of these stem cells, we may be able to rescue the heart defects in the mouse embryos," Dr. Conway said.
He's also putting other mouse models for persistent truncus arteriosus through the same analytical steps to see where their heart defects begin. "We are looking at developmental windows when these defects occur," he said. "Is there one common pathway that leads to this heart defect or are there lots of different pathways?" His guess is there will be multiple pathways leading to the same serious heart defect, primarily because birth defects in general are multifaceted.
It's important to identify each point at which the defect can occur so that methods can be explored to intervene at the trouble site or sites, potentially thwarting the defect. "If you can see where the heart defect first arises, you could have different therapies to circumvent it," Dr. Conway said.
Co-authors on the study published in Cardiovascular Research include second-year medical student Justin Bundy and research assistants Jinwen Chen, Eileen Dickman, Rhonda Rogers and Barbara M. Will.
The research was funded primarily by the National Institutes of Health.

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