Engineered Mesenchymal Stem Cells Make Blood Vessels that Help Heal Ailing Hearts

Another term for a heart attack is a myocardial infarction (MI). A heart attack or an MI occurs when the blood supply to the heart that flows through coronary blood vessels is interrupted. The interruption of blood flow deprives the heart of nourishment and oxygen, and the downstream blood vessels and heart muscle die as a result. The decrease in blood vessel density after a MI can increase cell death, which increases the amount of cell death and the size of the heart scar. Therefore, growing more blood vessels in the heart after a heart attack, which is known as therapeutic angiogenesis, is a potentially strategy in treating an MI (see Ziebart T, et al., (2008) Circ Res 103: 1327–1334)..

To this end, a few clinical trials have attempted to used stem cells that can make blood vessels to reverse heart damage caused by an MI (see Ripa RS, et al. (2007) Circulation 116: I24–I30 and Schachinger V, et al. (2006) N Engl J Med 355: 1210–21).

Among those therapeutic agents for heart attack patients, mesenchymal stem cells (MSCs) are considered excellent candidates. MSCs have the ability to differentiate into smooth muscle, or blood vessels, which means that they can help revascularize the heart after a MI. The problem with MSCs is their tendency to die off rapidly after transplantation into the heart after a heart attack (see Ziegelhoeffer T, et al. (2004) Circ Res 94: 230–38 & O’Neill TT, et al., Circ Res 97: 1027–35; & Perry TE, et al. (2009) Cardiovasc Res 84: 317–25).

To fix this problem, MSCs can be either preconditioned before implantation (see previous posts) or genetically engineered to withstand the hostile conditions inside the heart after a heart attack.

Previously, Muhammad Ashraf and Yigang Wang from the University of Cincinnati genetically engineered MSCs to express a surface protein called CXCR4.  CXC4R is the receptor for a chemokine known as CXCL12/SDF-1.  SDF-1 is a rather potent stem cell recruitment molecule.

When transplanted into the hearts of rodents that had just experienced a heart attack, MSCs that expressed CXCR4 showed increased mobilization and engraftment into the damaged areas of the heart. Also, the pumping abilities of the heart regions into which the MSC-CXCR4s were infused increased, and the MSC-CXCR4 cells cranked up their secretion of blood vessel-inducing growth factors (vascular endothelial growth factor-A or VEGF-A), This led to increased formation of new blood vessels and a decrease in the early signs of left ventricular remodeling (see Zhang D, et al. (2010) Am J Physiol Heart Circ Physiol 299: H1339– H1347; Huang W, et al. (2010) J Mol Cell Cardiol 48: 702–712; &.Zhang D, et al. (2008) J Mol Cell Cardiol 44: 281–292). While these papers show truly stunning results, it was still, even after all this work, unclear if the MSCs were actually differentiating into blood vessel cells and making blood vessels.

To nail this down, Wang and his group used a clever little technique. They engineered MSCs to express CXCR4 and the viral TK gene. TK stands for “thymidine kinase,” which is an enzyme involved in nucleotide synthesis from a virus. The TK enzyme is not found in human cells, and is therefore a target for antiviral drugs. If treated with antiviral drugs that target the TK enzyme, only cells with the TK gene will be killed.

When Wang and his group used their CXCR4-engineered MSCs to treat the heart of mice that had recently suffered a heart attack, they found that their hearts improved and that these same heart were covered with new blood vessels. However, when this experiment was repeated with CXCR4-MSCs that also had the TK gene, Wang his co-workers fed the mice a drug called ganciclovir, which kills only those cells that possess the TK gene. In these mice, their heart failed to improve and also were completely devoid of the new blood vessels.

This paper nicely shows that without viable MSCs, no new blood vessels were made. This strongly suggests that the engineered MSCs are differentiating into blood vessel cells and making new blood vessels, which helps the heart recover from the heart attack and shrinks the size of the dead area of the heart.

What are the implications for human clinical trial\? This is difficult to say. Before clinical trials with genetically engineered cells are approved those cells will need to go through piles of safety tests before they can be used in clinical trials. Once that hurdle is passed, then they can be used in human clinical trials, and they will certainly prove efficacious for human patients.