Fat-derived mesenchymal stem cells (MSCs) are easily procured and have the ability to differentiate into a variety of tissue, including heart muscle. When implanted into the hearts of laboratory animals, fat-derived MSCs induce the formation of new heart muscle and blood vessels and improve the function of the heart (Hwangbo, et al., Yonsei Med J 2010;51:69-76; Lin et al., J Transl Med 2010;8:88 & Yu, et al., Int J Cardiol 2010;139:166-172). Unfortunately, once implanted into the heart, the majority of cells undergo programmed cell death. The inhospitable environment of the heart after a heart attack is simply to hostile to support the growth and differentiation of these cells.
Are there ways to help the implanted cells and prevent them from dying before they have had a change to help the heart? The answer to this question is an unequivocal “yes.” MSCs can be genetically engineered to express a variety of molecules that help them resist hostile conditions (see Conrad P. Hodgkinson, et al., “Genetic Engineering of Mesenchymal Stem Cells and Its Application in Human Disease Therapy,” Hum Gene Ther. 2010; 21(11): 1513–1526). In one paper, Jun-jie Yang and colleagues in the laboratory of Yun-dai Chen in the Department of Cardiology at the Chinese PLA Hospital General Hospital engineered fat-derived MSCs with a gene called “heme oxygenase-1 (HO-1) to help the cells resist hostile conditions. They then used these engineered cells to treat heart attacks in rabbits.
The HO-1 gene encodes an enzyme that participates in dis-assembly of heme. Hemoglobin carries oxygen in the blood from the lungs to the tissues, and hemoglobin consists of a protein backbone known as the “globin” part of hemoglobin, and a flat, planar, molecule that holds an iron atom at its center known as “heme.” Hemoglobin is not the only protein that contains heme, since several other iron-utilizing proteins also possess heme groups for binding iron. When iron-utilizing binding proteins are degraded, the iron is removed and recycled, the protein portion is degraded and the amino acids that compose it are also recycled. Heme, however, is not recycled. Free heme is damaging to the cell, and heme is degraded in two reactions to bilirubin. The enzymes that degrade heme are heme oxygenase (which converts heme to biliverdin) and biliverdin reductase (which converts biliverdin to bilirubin. In our bodies, bilirubin is conjugated to acidic sugar, which increases its solubility and allows excretion.
Cells with high levels of HO-1 are able to endure higher levels of stress and adverse conditions. As it turns out, HO-1 degrades many other things besides heme, and this seems to be the reason why HO-1 confers on cells a greater ability to withstand stressful conditions (see Shibahara, Tohoku J Exp Med 2003;200:167-86 & Zeng B., et al., J Biomed Sci 2010;17:80).
In this paper, three groups of nine rabbits were given a echocardiogram, which measures the activity of the heart muscle and then two of the groups were given liposuction, and then rabbits in all three groups were given heart attacks. The fat-derived MSCs were isolated and cultured, and the MSCs from the first group were transduced with HO-1. Then 13 days after the induction of the heart attack, all the rabbits were given a second echocardiogram and then 14 days after the heart attack, the rabbits were given either MSCs transduced with HO-1, MSCs, or buffer with no cells. All MSCs were directly injected into the heart muscle. Then 42 days after the induction of the heart attack, all 27 rabbits were given a final echocardiogram and then sacrificed for tissue examinations of the hearts..
The results showed that the Ho-1 engineered MSCs were much less likely to die and also showed a greater ability to resist hydrogen peroxide, an agent that is known to kill cells. When the hearts from the three groups were examined, it was clear that before the cell treatments, there were no functional differences between the hearts in the animals of either group. However, 42 days after induction of the heart attack, and one month after cell treatment, the hearts of the HO-1/MSC group had smaller areas of dead cells, great blood vessel density, greater connectivity between the heart muscle cells, and better innervation by the sympathetic nervous system.
Even though both groups that received MSCs showed better functioning hearts than those in the control group that received only buffer injections,l the HO-1/MSC group had hearts that were functionally superior to those in the MSC only group. Tissue examinations of the hearts of animals from the HO-1/MSC group also showed staining in the injected areas for proteins associated with blood vessels and heart muscle. This strongly suggests that the implanted fat-derived MSCs are differentiating into heart muscle and blood vessels.
These data show that even though MSC implantations can improve the function of hearts from laboratory animals that have suffered heart attacks, engineered MSCs can improve the heart even more and are safe and efficacious. Hopefully, this will spur the FDA to approve human clinical trials that use engineered MSCs for heart attack patients.