Heart Cells Expressing Stem Cell Factor Show Less Cell Death After a Heart Attack


Stem Cell Factor is a cell surface protein that is expressed by several different cells, including tissue fibroblasts, heart cells, cells in the bone marrow, and blood vessel cells. Stem Cell Factor (SCF) plays important roles in the migration, proliferation, and adhesion of any cell that expresses the receptor for SCF, a molecule called c-kit. Cells that express c-kit include cardiac stem cells, endothelial progenitor cells, and hematopoietic stem cells. When c-kit binds to SCF, the SCF-containing cell activate their Akt /PI3K pathway, and this pathway prevents cells from dying and drives them to divide, differentiate, more, adhere, and even secrete new molecules.

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Fu-Li Xang in the laboratory of Qingping Feng at the University of Western Ontario has done several experiments with SCF in the heart. His goal is to determine if heart cells that have SCF fare better after a heart attack than hearts that do not have quite so much SCF.

To that end, Feng and his team showed that SCF does help heal the heart after a heart attack in 2009 (Xiang et al, Circulation 120: 1065-74). The next step was to determine if SCF could attenuate cell death in the heart that results from a heart attack.

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The strategy behind this experiments involved making genetically engineered mice that expressed lots of SCF in their heart muscle. The particular mouse strain that Feng and his crew made had the SCF gene activated by a heart muscle-specific promoter, but the expression of SCF could be shut off by giving the mice the drug doxycycline. These SCF transgenic mice and normal mice were given heart attacks and then some were treated with a doxycycline while others were given a drug called LY294002, which inhibits the Akt pathway. These animals were then analyzed three hours after the induced heart attack and the amount of cell death, the size of the infact, the number of stem cells that moved into the heart were all measured.

 LY294002
LY294002

The upshot of all this work is this: SCF decreased the amount of cell death by about 40%. Also the size of the infarct was also smaller. These benefits were abrogated by the co-administration of either doxycycline or LY294002. When a search for molecules that are indicative of cell death were examined, the results were completely unsurprising: the markers of cells death like fragmented DNA or caspase-3 were decreased in the SCF mice and this attenuation was abrogated by co-administration with doxycycline or LY294002.

Other experiments examined the activation of the Akt/PI3K pathway in the SCF-expressing animals, and it was quite clear that the SCF-expressing animals showed a robustly active Akt/PI3K pathway compared to the non-SCF-expressing mice.

A different experiment examined the presence of c-kit-expressing cells in the hearts of these mice. Remember that c-kit expressing cells are stem cells that have been recruited to the heart by the SCF. Once again, it was exceedingly clear that the SCF-expressing mice had hearts with a large excess of c-kit-expressing cells and this recruitment of stem cells was abrogated by neutralizing c-kit with an antibody against it. The incoming stem cells also tend to secrete a host of interesting molecules that help heal the heart, and one of these molecules, HGF (hepatic growth factor), which also goes up in concentration in the hearts of the SCF-expressing mice, is blocked by a drug called crizotinib. If SCF-expressing mice were pre-treated with crizotinib, the infarct size tended to be just as large as the non-SCF-expressing cells.

Feng and his group also examined the resident stem cells in the heart, the cardiac stem cells population, which, by the way, also express c-kit. These cells also were induced to express HGF and IGF (insulin-like growth factor) as a result of SCF, and if the c-kit receptor was blocked with an antibody, then this effect was abrogated.

There is a lot of data in this paper, but the news is almost all good. Basically SCF will recruit stem cells to the heart after a heart attack and this recruitment happens quickly (within 3 hours) and does the heart a world of good. Translating this work into human patients will not be easy, but SCF is available. If it could be localized to the heart by some means soon after a heart attack, there is good reason to believe, based on these pre-clinical results that it would do the patient quite a bit of good. The next piece is figuring our how to go about doing just that.

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Published by

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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