Researchers at Memorial Sloan-Kettering Cancer Center report that 15 embryonic stem cells injected into early embryos of mice whose hearts were genetically predisposed to develop a lethal defect, rescued the heart from developing the disorder by not only producing normal daughter cells that were incorporated into the defective embryonic heart but also by releasing biological factors into the nearby vicinity. This prevented neighboring heart cells from developing into defective tissue.
"In other words, stem cells act like nurses, restoring 'sick' cells to health" said Robert Benezra, Ph.D., a Member in the Cancer Biology and Genetics Program at Memorial Sloan-Kettering Cancer Center and the study's senior author. "The result was that fifty-percent of the mice fated to die in the womb were born with healthy hearts."
In previous studies, Dr. Benezra and colleagues demonstrated a relationship between the presence of a specific protein called Id during embryonic growth and the normal development of capillaries and blood vessels. Mice engineered without this protein, called Id "knock-out" mice, display severe cardiac defects and die at mid-gestation.
"In this current study, with the repair of congenital heart defects in our Id knockout embryos, we observed that the stem cells provided normal signals to themselves and also to their neighbor cells to correct the organ as a whole," explained Diego Fraidenraich, Ph.D., the study's lead author.
The researchers also found a relationship between the Id protein and stem cells. "We found that stem cells are critically dependent on the Id protein for self-renewal and differentiation," added Dr. Benezra. "A reduction of just 15-20 percent of the Id protein impairs the stem cells' ability to rescue these embryonic mouse heart cells. These cells are very powerful, but also apparently very delicate."
To understand the molecular basis of the rescue, the authors identified two important molecules implicated in signaling from the ES cells to the Id knock-out cells. These molecules are insulin-like growth factor 1 (IGF-I) and WNT5a. The former molecule is a long-range acting factor, and the latter is a short-range factor and a member of the family of WNT proteins. Both molecules are implicated in heart development and cancer.
The authors demonstrated that IGF-I injected into the mother can cross the placenta and influence fetal cardiac development in the Id knock-out embryo. The Id knock-out embryos were born, but with partial rescue of cardiac defects and abnormal gene expression profiles. As a result, Id knock-out pups whose mothers were manipulated bypassed mid-gestation lethality, although they died during the first two days of life. On the other hand, WNT5a had the ability to correct the abnormal gene expression profiles of the Id knock-out hearts to normal levels. These two mechanisms (long- and short- range action) in conjunction may account for the full correction of the cardiac defects.
The study was co-authored by Elizabeth E. Stillwell, PhD, Elizabeth E. Romero and Katia Manova, PhD from Memorial Sloan-Kettering Cancer Center, and Craig T. Basson, MD, PhD and David Wilkes, PhD from Weill Medical College of Cornell University.
The National Institutes of Health has supported this research, by funding Dr. Diego Fraidenraich through a mentored minority faculty development award (Heart, Lung and Blood Institute) and Dr. Robert Benezra (National Cancer Institute). Dr. Basson is an Established Investigator of the American Heart Association and is also funded by the Snart Cardiovascular Fund.