Sunday, 3 October 2010

Researchers Engineer Adult Stem Cells That Do Not Age

Bone marrow stem cells injected into skeletal muscle reverse heart failure
Sunday, 03 October 2010

Biomedical researchers at the University at Buffalo have engineered adult stem cells that scientists can grow continuously in culture, a discovery that could speed development of cost-effective treatments for diseases including heart disease, diabetes, immune disorders and neurodegenerative diseases.

UB scientists created the new cell lines – named "MSC Universal" – by genetically altering mesenchymal stem cells, which are found in bone marrow and can differentiate into cell types including bone, cartilage, muscle, fat, and beta-pancreatic islet cells. They identified a growth-factor chain of action that prompts bone marrow stem cells to repair cardiac tissue and reverse heart failure.

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.

Biomedical researchers at the University
at Buffalo have engineered adult stem cells
that scientists can grow continuously in
culture. Credit: Douglas Levere,
University at Buffalo, NY.
The current findings provide insight into how the injected stem cells may rejuvenate the host tissue.

"By thoroughly understanding the interplay of stem cells and host tissue, and characterizing stem-cell-derived growth factors, 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," says Techung Lee, PhD, senior author.

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 researchers say the breakthrough overcomes a frustrating barrier to progress in the field of regenerative medicine: the difficulty of growing adult stem cells for clinical applications.

Because mesenchymal stem cells have a limited life span in laboratory cultures, scientists and doctors who use the cells in research and treatments must continuously obtain fresh samples from bone marrow donors, a process both expensive and time-consuming. In addition, mesenchymal stem cells from different donors can vary in performance.

The cells that UB researchers modified show no signs of aging in culture, but otherwise appear to function as regular mesenchymal stem cells do – including by conferring therapeutic benefits in an animal study of heart disease. Despite their propensity to proliferate in the laboratory, MSC-Universal cells did not form tumours in animal testing.

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.

"Our stem cell research is application-driven," says Techung Lee.

"If you want to make stem cell therapies feasible, affordable and reproducible, we know you have to overcome a few hurdles. Part of the problem in our health care industry is that you have a treatment, but it often costs too much. In the case of stem cell treatments, isolating stem cells is very expensive. The cells we have engineered grow continuously in the laboratory, which brings down the price of treatments."

Stem cells help regenerate or repair damaged tissues, primarily by releasing growth factors that encourage existing cells in the human body to function and grow.

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.

UB has applied for a patent to protect Lee's discovery, and the university's Office of Science, Technology Transfer and Economic Outreach (UB STOR) is discussing potential license agreements with companies interested in commercializing MSC-Universal.

Lee's ongoing work indicates that this feature makes it feasible to repair tissue damage by injecting mesenchymal stem cells into skeletal muscle, a less invasive procedure than injecting the cells directly into an organ requiring repair. In a rodent model of heart failure, Lee and collaborators showed that intramuscular delivery of mesenchymal stem cells improved heart chamber function and reduced scar tissue formation.

UB STOR commercialization manager Michael Fowler believes MSC-Universal could be key to bringing new regenerative therapies to the market. The modified cells could provide health care professionals and pharmaceutical companies with an unlimited supply of stem cells for therapeutic purposes, Fowler says.

Lee says his research team has generated two lines of MSC-Universal cells: a human line and a porcine line. Using the engineering technique he and colleagues developed, scientists can generate an MSC-Universal line from any donor sample of mesenchymal stem cells, he says.

"I imagine that if these cells become routinely used in the future, one can generate a line from each ethnic group for each gender for people to choose from," Lee says.

Source: Adapted from Press releases from University at Buffalo, State University of New York.
Contact: Charlotte Hsu and Lois Baker.

Activation of host tissue trophic factors through JAK/STAT3 signaling: A mechanism of mesenchymal stem cell-mediated cardiac repair
Shabbir A, Zisa D, Lin H, Mastri M, Roloff G, Suzuki G, Lee T
Am J Physiol Heart Circ Physiol. 2010 Sep 17, doi:10.1152/ajpheart.00488.2010


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