Heart stem cell therapy after a major heart attack holds the promise of helping to repair severely damaged cells by encouraging the growth of new ones. However, the process which involves infusing healthy stem cells into the heart to replace the damaged tissue has had limited success in clinical trials.

In order to get the most benefit from heart stem cell treatment, it is essential for doctors to properly place the cells in the heart. But, once the stem cells are injected, its difficult to determine exactly where they wind up, and many scientists believe faulty placement is ultimately the culprit of the therapys disappointing results.

Now, that problem could be potentially solved with a new visualization technique developed by Dr. Sam Gambhir and fellow researchers at Stanford University School of Medicine in California. Their study, published in Science Translational Medicine, details the invention of silica nanoparticles, which can be injected inside stem cells, acting as tiny tracking devices that allow doctors to see the stem cells path inside the body.

According to the studys researchers, the most encouraging results from heart stem cell therapy have been seen after bypass surgery, which is done right after a patient has suffered a heart attack. If performed correctly, stem cell injections can encourage new cell proliferation and help increase blood flow up to 10 percent.

To get the most benefit, doctors have to find the perfect place in which the cells will do the most work.

The best place is the region (in the heart) between the damaged tissue and the healthy tissue, Jesse Jokerst, a postdoctoral fellow in the Stanford Molecular Imaging Scholars Program and one of the studys authors, told FoxNews.com. Thats where the most therapeutic benefit can occur. When placed there, the stem cells can take advantage of the blood flow in the healthy region, but can effect a change in the diseased region.

In order to determine where to place the cells, physicians currently take images of the heart through magnetic resonance imaging (MRI) one image before the injection to estimate placement, and a second image after the injection to see how the cells have developed. But the time period between the capture of those pictures leaves a lot to be desired, as the stem cells do not have a unique signature that allows doctors to differentiate between them and the normal heart cells.

Feeling somewhat blind, the doctors have many questions once the stem cells are injected. Did they reach their intended target? Did they remain at the heart wall? How many cells actually stayed and how many diffused or died? Inevitably, the doctors have to wait weeks following the stem cell injection to get their questions answered, by observing if heart function improved.

Making a stem cell 'movie'

Frustrated by those time constraints, the researchers realized all their questions could be answered a lot faster and much more accurately through ultrasound imaging.

The rest is here:
New nano-'tracking devices' allow doctors to visualize stem cells inside hearts

Public release date: 20-Mar-2013 [ | E-mail | Share ]

Contact: Bruce Goldman goldmanb@stanford.edu 650-725-2106 Stanford University Medical Center

STANFORD, Calif. The promise of repairing damaged hearts through regenerative medicine infusing stem cells into the heart in the hope that these cells will replace worn out or damaged tissue has yet to meet with clinical success. But a highly sensitive visualization technique developed by Stanford University School of Medicine scientists may help speed that promise's realization.

The technique is described in a study to be published March 20 in Science Translational Medicine. Testing the new imaging method in humans is probably three to five years off.

Human and animal trials in which stem cells were injected into cardiac tissue to treat severe heart attacks or substantial heart failure have largely yielded poor results, said Sam Gambhir, PhD, MD, senior author of the study and professor and chair of radiology. "We're arguing that the failure is at least partly due to faulty initial placement," he said. "You can use ultrasound to visualize the needle through which you deliver stem cells to the heart. But once those cells leave the needle, you've lost track of them."

As a result, key questions go unanswered: Did the cells actually get to the heart wall? If they did, did they stay there, or did they diffuse away from the heart? If they got there and remained there, for how long did they stay alive? Did they replicate and develop into heart tissue?

"All stem cell researchers want to get the cells to the target site, but up until now they've had to shoot blindly," said Gambhir, who is also the Virginia and D.K. Ludwig Professor in Cancer Research and director of the Molecular Imaging Program at Stanford. "With this new technology, they wouldn't have to. For the first time, they would be able to observe in real time exactly where the stem cells they've injected are going and monitor them afterward. If you inject stem cells into a person and don't see improvement, this technique could help you figure out why and tweak your approach to make the therapy better."

Therapeutic stem cells' vague initial positioning is just part of the problem. No "signature" distinguishes these cells from other cells in the patient's body, so once released from the needle tip they can't be tracked afterward. If, in the weeks following stem cells' infusion into the heart, its beating rhythm or pumping prowess has failed to improve so far, more often the case than not you don't know why. That ambiguity, perpetuated by the absence of decent imaging tools, stifles researchers' ability to optimize their therapeutic approach.

The new technique employs a trick that marks stem cells so they can be tracked by standard ultrasound as they're squeezed out of the needle, allowing their more precise guidance to the spot they're intended to go, and then monitored by magnetic-resonance imaging for weeks afterward.

To make this possible, the Gambhir lab designed and produced a specialized imaging agent in the form of nanoparticles whose diameters clustered in the vicinity of just below one-third of a micron less than one-three-thousandth the width of a human hair, or one-thirtieth the diameter of a red blood cell. The acoustical characteristics of the nanoparticles' chief constituent, silica, allowed them to be visualized by ultrasound; they were also doped with the rare-earth element gadolinium, an MRI contrast agent.

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Stem cells entering heart can be tracked with nano-'hitchhikers,' Stanford scientists say

For organisms to develop and grow, asymmetry is essential. New research from Howard Hughes Medical Institute scientists reveals how a localized source of a signaling molecule directs a dividing stem cell to produce two different cellsone identical to its parent, the other a more specialized cell typeand aligns those cells. In a developing tissue, such oriented divisions will position cells to migrate to the right place to ensure the right architecture.

This kind of asymmetry is a universal aspect of how organisms grow, says Roel Nusse, an HHMI investigator at Stanford University, explaining that dividing cells must orient themselves appropriately to create the asymmetrical bodies of complex organisms. In a paper published March 21, 2013, in the journal Science, Nusse and his collaborators show that a protein called Wnt3a coordinates the orientation of the two different cell types that are generated when a dividing stem cell undergoes an asymmetrical division.

Theres all kinds of geometry going on, regulated by the signals between cells. But when you add growth factors to a tissue culture medium, theres no orientation effect. Roel Nusse

Stem cell division with Wnt-3a bead: When grown with a Wnt3a-coated bead (blue), embryonic stem cells divide such that one daughter cell is proximal to the Wnt3a signal, and the other daughter cell is distal to the signal. Segregating chromosomes of the dividing cell are seen in orange.

From: Habib, S.J., Chen, B., Tsai, F., Anastassiadis, K., Meyer, T., Betzig, E., and Nusse, R. 2013. Science.

Wnt3a is one of a large family of Wnt proteins that play important roles in controlling how organisms develop and grow. Nusse and Harold Varmus discovered the first Wnt gene in mice in Varmuss lab at the University of California, San Francisco in 1982. Since then, Nusse and others have shown that Wnt proteins play key roles in embryonic development, tissue regeneration, bone growth, stem cell differentiation, as well as many human cancers.

To study how Wnt proteins affect cells, researchers typically add the molecule to the nutrient-rich solution in which laboratory-cultured cells are grown. Nusse and his team recently showed that when Wnt3a is given to embryonic stem cells in this way, it helps the cells maintain their identity as stem cells, rather than differentiating into more specialized cells. But experiments like these dont really reflect the ways cells in a living organism receive signals, Nusse says.

Most of the signals that cells in tissues make for each other are received by neighboring cells, he says. So theres an orientation effect: the signal comes from one end of the cell and it only activates the target cell at one side. Theres all kinds of geometry going on, regulated by the signals between cells. But when you add growth factors to a tissue culture medium, theres no orientation effect.

Shukry Habib, a postdoctoral researcher in Nusses lab, came up with a way to recreate that orientation effect with cells grown in a dish. Rather than adding Wnt3a to the tissue culture medium, he attached it to tiny beads. When he added the Wnt-coated beads to dishes in which embryonic stem cells were growing, the scientists could then watch individual cells that were close enough to a bead to receive a Wnt3a signal, and track the fate of the new cells as they divided.

Nusse says the first experiments with the Wnt3a beads were underway when he attended a meeting of HHMI scientists and met with Eric Betzig, a lab head at the Janelia Farm Research Campus. In 2011, Betzigs team developed a high-speed, high-resolution, three-dimensional imaging technology that they call the Bessel beam plane illumination microscope. The microscope gives extraordinarily detailed views of cellular processes in action, and as Betzig and Nusse talked, they realized it could be a powerful tool in tracking the stem cells response to the Wnt-coated beads.

Originally posted here:
Wnt Signal Regulates the Geometry of Dividing Stem Cells