Genetically Engineered Bone Marrow Stem Cells on a Fibrin Patch Repairs Damaged Heart


Regenerative therapies for the heart have come a long way from the first clinical trials and injected bone marrow cells directly into the heart muscle. Despite the modest improvements shown in those earlier studies, it became clear that the vast majority of cells that were implanted into the heart died soon after their introduction. This single fact left researchers looking for a better way to deliver cells into the damaged heart.

Several laboratories have tried to condition the stem cells before their injection in order to “toughen them up” so that they do not tend to die so easily. While these experiments have worked well in laboratory animals, no clinical trials have been conducted to date with conditioned stem cells. Another strategy is to place the cells on a patch that is then applied to the dead heart tissue in order to promote healing of the heart.

The patch strategy was employed by Hao Lai and Christopher Wang and their co-workers at the Shanghai Institute of Cardiovascular Disease in Shanghai, China. Lai and others extracted bone marrow stem cells from the bones of Shanghai white pigs. These cells were cultured, and genetically engineered to expressed IGF-1 (insulin-like growth factor-1). Once IGF-1 expression was confirmed, the cells were loaded onto a fibrin patch and placed over the hearts of Shanghai white pigs that had just experienced laboratory-induced heart attacks. There were four groups of pigs: 1) those treated with fibrin patches with bone marrow stem cells that were not genetically engineered; 2) another group treated with fibrin patches that contained genetically engineered bone marrow stem cells that did not express IGF-1; 3) fibrin patches containing bone marrow stem cells that had been engineered to express IGF-1; and 4) a control group that was not treated with any cells or patches.

In culture, the IGF-1 engineered cells did not differentiate into heart muscle cells, and they did induce proliferation in Human Umbilical Vein Endothelial cells, which suggests that these engineered cells would induce the formation of new blood vessels.

When transplanted into heart injured pigs, the IGF-1-expressing cells on a fibrin patch significantly reduced the size of the infarct in the hearts, and increased the thickening of the walls of the heart. Gene expression studies showed that the IGF-1-expressing cells on the fibrin patch induced anti-cell death genes that promote cell survival. These cells also induced the growth of many new blood vessels and seemed to promote the growth of new heart muscle, but the cells on the patch are almost certainly not the source of these new cells, but resident stem cell populations in the heart probably were.  The increase in heart mass suggests that the implanted cells induced the resident stem cell populations in the heart to divide and differentiate into heart muscle cells.

This new technique proved safe and effective. It prevented remodeling (enlargement) of the heart and promoted cell survival. It is a technique that shows promise, especially since the fibrin patch is biodegradable and the bone marrow stem cells will not last indefinitely in the heart. These cells simply work by serving as a platform for the secretion of IGF-1 and perhaps other healing molecules.

Another caveat of this experiment is that the bone marrow stem cells were genetically engineered with lentivirus vectors. Because of the tendency for these vectors to insert genes willy-nilly into the genome, this is almost certainly not the safest way to genetically modify cells Finally, the improvements in these animals was significant albeit modest. In order for this technique to come to the clinic, it will have to induce better improvements in heart function. There were modest, albeit insignificant increases in ejection fraction. The ejection fraction will need to be increases for this technique to have a fighting chance to come to clinical trials. Nevertheless, this is a fine start to what might become a new strategy to treat patients with ailing hearts.

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mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).

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