Researchers Discover How Bone Marrow Stem Cells Injected Into Skeletal Muscle Reverse Heart Failure

BUFFALO, NY – A growth-factor chain of action that prompts bone marrow stem cells to repair cardiac tissue and reverse heart failure has been identified by researchers at the University at Buffalo's Center for Research in Cardiovascular Medicine.

Earlier research from this group showed for the first time that injecting mesenchymal (bone marrow) stem cells into skeletal muscle in an animal model increased two-fold the production of myocytes, a type of heart muscle cell.

The current findings provide insight into how the injected stem cells may rejuvenate the host tissue. Results of the discovery of this distinct heart repair action appear online as an article-in-press in the American Journal of Physiology-Heart Circulation Physiology at http://www.ncbi.nlm.nih.gov/pubmed/20852053

"By thoroughly understanding the interplay of stem cells and host tissue, and characterizing stem-cell-derived growth factors," says Techung Lee, PhD, senior author on both papers, "it is possible to assemble a cocktail of these factors and use it for tissue repair, much like the use of insulin for diabetes patients."

Lee is associate professor of biochemistry and biomedical engineering in the UB School of Medicine and Biomedical Sciences and the School of Engineering and Applied Sciences, respectively.

Bone marrow mesenchymal stem cells [MSCs] possess an impressive ability to produce a plethora of growth factors, most of which remain to be characterized, Lee says.

"These growth factors appear to account for most of the observed therapeutic benefits in preclinical and clinical studies. Using skeletal muscle as a depot for the injected MSCs, we found that the MSC-derived growth factors activate production of host muscle tissue-derived growth factors."

The heart disease death rate has dropped significantly in the last three decades due to better treatments, resulting in large numbers of people living with heart failure. However, heart transplantation is the only therapy currently available to reverse the continual decline in heart function, and donor hearts are scarce.

Lee notes that current clinical trials of myocardial stem cell therapy require surgery, injecting the cells directly into the heart or into the heart muscle, invasive methods that can result in harmful scar tissue, arrhythmia, calcification or small vessel blockages. Lee's research group found that only 1-to-2 percent of MSCs infused into the myocardium actually grafted into the heart, and there was no evidence that they differentiated into heart muscle cells.

"For these reasons, and because patients with heart failure are not good surgical risks, it made sense to explore a non-invasive cell delivery approach," Lee notes.

Lee's group has shown that the instructive signal that generates the repair of cardiac tissue appears to come from at least a group of MSC-derived factors belonging to the IL-6 type cytokine family. Cytokines are small proteins made by the cells that act on other cells to stimulate or inhibit their function.

"These IL-6 type cytokines typically activate their cell/tissue targets through two specific proteins, known as JAK and STAT3, a cytosolic and a nuclear protein, respectively," explains Lee. "These cytokines then instruct the host cell to produce another panel of growth factors.

"The combined effects of the growth factors from injected stem cells and growth factors produced by host tissues cause tissue repair and achieve healing. Being able to use the factors for therapy rather than stem cells will make therapy to repair hearts much easier," he says.

Arsalan Shabbir, David Zisa, Huey Lin, Michalis Mastri, Gregory Roloff, and Gen Suzuki, all from UB, also contributed to the study.

The research is supported by a grant from the National Institutes of Health.

The University at Buffalo is a premier research-intensive public university, a flagship institution in the State University of New York system and its largest and most comprehensive campus. UB's more than 28,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.