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Time-Traveling Cells

experts eager to harness the power of stem cells are exploring how to send adult cells back in time—and leverage their therapeutic potential

Cells have the ability to travel into the past.

"Genetics holds the key," says Case Western Reserve University biomedical engineer Horst von Recum, PhD. "Identify which 'switches' have been flipped to become adult cells and then flip them back to the embryonic state."

This kind of reprogramming results in cells that resemble embryonic stem cells. As their name suggests, embryonic stem cells come from embryos and can develop into any of the cell types that make up the adult body, opening the doors to much-hoped-for regenerative or reparative therapies.

Time-Traveling Cells

Stem cells have the ability to develop into any of the cell types that make up the body. Photo: Courtesy of Paul Tesar, PhD

To this end, cellular time travel is rife with potential. Cells that have reverted, also called induced pluripotent stem cells, could prove to be as adaptable as controversial embryonic stem cells but could be taken from a patient's own body. They would supply nearly perfectly matched tissues and help avoid rejection by a patient's immune system.

"Theoretically, I could make a personalized tissue bank out of my own cells—or, if I had a genetic problem, the cells of a sibling or another well-matched donor—and construct a new heart out of these cells," von Recum imagines.

Such tissue banks could be the next frontier in personalized medicine and a goal that, if achieved, would supply replacement cells and tissues for a range of medical conditions, including Parkinson's disease, spinal cord injuries, diabetes, stroke and heart disease.

But to reach this frontier, researchers first must find a way to reliably predict or control the kind of specialized cell that a clean-slate embryonic stem cell will become.

"We still don't fully understand how stem cells change or 'differentiate,'" von Recum says. "We need to know how they develop into specialized tissue so we can harness their power. Or we need a way around it."

That's why von Recum is examining the fundamental process of a cell's differentiation out of its embryonic state.

"What exactly goes on as stem cells differentiate?" he wonders, noting that stem cells seem to have a mind of their own about what kind of adult cells they will become.

Studies into differentiation are exciting but very preliminary, and scientists are far from a clear understanding. A Phase I safety trial in patients with recent spinal cord injuries, approved by the Federal Drug Administration in January, is the first human trial of embryonic-stem-cell derived cells. This trial-in which Case Western Reserve University is not involved-was put on hold in August by the FDA to await further laboratory data. Only a handful of patients will participate in the trial, examining whether the implanted cells develop tumors or cause damage to their nervous systems when injected.

"There's a 'black box' between stem cells and differentiated cells," says Paul Tesar, PhD, a stem-cell expert at Case Western Reserve's School of Medicine. "We want to develop a clear understanding of how the cells go from the embryonic stem cell state to a functional state so that we can reproducibly take a stem cell and differentiate it into specific, therapeutically useful cells."

To do this, von Recum is using stem cells to watch biological decision making in action with a tool known as "fluorescent proteins." The proteins track a cell's differentiation into a specialized cell by causing cells to appear green or red when viewed through a special fluorescence microscope.

"This 'red light, green light' process marks the cells that we're interested in green, while other cells appear red," von Recum explains. "We can keep green cells for further study and eventually therapy."

Using fluorescent proteins to indicate when genes are expressed is not unconventional-but using them to better understand the way stem cells differentiate is.

"The intriguing aspect of von Recum's effort is the interface of engineering and stem cells," says fellow stem cell researcher Stanton Gerson, MD, director of Ohio's Center for Stem Cell and Regenerative Medicine. "He's using a very structured, rational approach, thinking of stem cells in the context of a unique engineering model."

The approach is key to researchers' "time travel" work with adult cells, work that holds tremendous allure for opponents of embryonic stem cell research, many of whom believe that an embryo is a human being and that destruction of that embryo, even for medical research, is morally wrong.

So why not avoid controversy altogether and explore this avenue for stem cell research exclusively?

"The field of induced pluripotent stem cells attempts to do exactly that," von Recum says. "However that field is still in its infancy."

Human-induced pluripotent stem cells first developed in the laboratory as recently as late 2007. Researchers initially zeroed in on four genes that could be inserted into mature cells to reprogram them to become more like embryonic stem cells. But the virus scientists used early on could lead to cell death or tumors if the altered cells were used as medical therapies. More recently, researchers found a way to derive induced pluripotent stem cells without the viruses that could disrupt the genes.

This year, Mayo Clinic investigators showed that certain adult cells called fibroblasts, which can cause scarring after heart attack and other injury, could be reprogrammed into stem cells that improved the functioning of damaged hearts in laboratory subjects. Yet, despite remarkable scientific strides, much more investigation is still needed on the potential therapeutic applications of induced pluripotent stem cells.

Stem cells could offer new options for treating patients who have congestive heart failure or who have had heart attacks. Photo: Courtesy of Paul Tesar, PhD

G. Russell Reiss, MD, a cardiothoracic surgeon and stem cell researcher with the Department of Veterans Affairs' Salt Lake City Health Care System, along with his peers in the field, is looking for other ways to develop stem cell-based regenerative therapies.

New approaches are needed, he says, to address cardiovascular disease, in light of the limited options today for treating people with congestive heart failure and those who have had a heart attack from a blocked blood supply. The approaches over the last 50 years, including drug therapy and surgery, have amounted to "putting a Band-Aid on a very big problem and not addressing the heart's long-term recovery," he adds. Current options, he says, boil down to "go to the operating room and restore the blood supply to the heart with stents and surgery to open up or bypass blocked blood vessels."

For those whose hearts are severely weakened to the point of requiring a transplant, donor hearts are hard to come by and can require many months on a waiting list. Human stem cells could be an alternative to stents, scalpels and few-and-far-between donor hearts.

Von Recum, who also studies cardiovascular disease, wants to build heart cells, too, but he also wants to build three-dimensional blood vessels that can deliver an ample, unrestricted blood supply to the heart. Growing heart cells in a hard plastic culture dish is one thing-a complex task in itself-but building three-dimensional blood vessels requires coaxing the cells into shaping themselves as they would in the developing embryo.

To encourage cells to act as they would in their natural environment, von Recum has replaced the hard plastic dish with a more true-to-life "polymer scaffold" that includes a special version of flexible silicone rubber.

Using a vacuum pump, the high-tech membrane is stretched rhythmically to simulate a heartbeat (imagine inflating and deflating a balloon, with cells grown on its surface). The cells, which are already contracting on their own, adapt to the membrane and begin "to beat and act remarkably like a heart," von Recum describes. The cell sheet can be removed from this special silicone rubber without breaking up, an essential step toward transplantation into the body.

The successful development of these blood-vessel precursors encourages researchers in the field, who increasingly view regenerative medicine as the best-chance therapeutic strategy to transform heart disease treatment in coming years.

"Stem cells could allow us not only to stop disease progression or treat symptoms, like heart surgery and many pharmaceuticals today, but also to heal the heart moving forward," says researcher Reiss.

As for when patients and their families might begin to see the benefits, Case Western Reserve's Tesar says, "It's unfair to predict a timeframe for these kinds of scientific advances. There are novel challenges ahead. "But the potential is real."

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