Techniques for tracking stem cells necessary for possible therapies

Last week The Scientist carried a story addressing a topic near and dear to the heart of anyone trying to develop a therapy based on transplanting stem cells, whether they are embryonic, adult, or iPS cells: Where do the cells go once they are transplanted?

The problem is this — if you, as a scientist, transplant stem cells near some damage that you are hoping they will repair, you've got to hope those cells actually make it to the damaged tissue. If they make a run for the liver when you are trying to treat the heart, or simply sit in a lump where you implanted them, those cells aren't going to fulfill their mission.

The story quotes CIRM grantee Joseph Wu of Stanford University who has SEED and Basic Biology III Awards to detect stem cells implanted into the heart and to develop stem cell transplantation therapies for hypertrophic cardiomyopathy.

“If you want to understand what happens to these stem cells, it’s important to track the fate of these cells without having to kill the animal,” says Joseph Wu, a cardiologist at Stanford University School of Medicine in Palo Alto, California. Stem cell transplants may settle down, proliferate, and differentiate as desired; they may form dangerous tumors; or they may simply falter and die.

The issue is also one CIRM grantee Paul Knoepfler of the University of California, Davis, touched on in his blog last week, saying:

Once these cells, which have spent weeks in a lab environment, are injected into a person, what happens next?

This is arguably the most important question in the regenerative medicine field, but there are few answers. We are literally mostly in the dark about what cells do after transplant, but there are some things that can be predicted pretty confidently.

He goes on to discuss some of what's known about the issue using Geron's clinical trial as an example.

In their article, the Scientist discusses a few techniques scientists are using (including some nice images) to address the question of where the cells go. The story includes a technique being used by CIRM grantee Eduardo Marban at Cedars-Sinai Medical Institute, who has a Disease Team Award to develop a therapy for heart disease.

This is the type of research that comes to mind when people who don't follow the science comment on the lack of cures. CIRM is funding a broad range of science, some of which is primarily dedicated developing new therapies, and some of which is working to understand these kinds of basic questions that need to be addressed before those therapies can become widespread.

A.A.

Virus-free Technique Yields Pluripotent Stem Cells

Stem cells in fat hold intrigue for scientists because most of us have excess to spare, and the cells seem to be quite versatile. Now a team at Stanford has found a way to transform them into induced pluripotent stem (iPS) cells without using potentially dangerous viruses to carry the reprogramming genes into the cells.

This paper marks another step toward the holy grail of reprogramming, which is to find a safe, efficient way of returning adult cells to their embryonic-like state, called pluripotency. So far, most techniques are either not efficient or require inserting genes that may make the cells unsafe for therapeutic use.

The team used so-called minicircles of DNA to reprogram the cells into pluripotency. These minicircles contain just the four genes needed to transform the cells along with a fluorescence gene that allows the cells to be tracked. The minicricles are about half the size of naturally occurring plasmid rings that have been used in some other iPS transformations, and unlike integrating viruses, the minicircles do not get replicated as the cells multiply so the extra genes are lost over time, making the cells safer for therapy.

A press release from Stanford University quoted co-author Michael Longaker saying:

“This technique is not only safer, it’s relatively simple. It will be a relatively straightforward process for labs around the world to begin using this technique. We are moving toward clinically applicable regenerative medicine.”

Another co-author, Mark Kay, developed the minicircle technology a few years ago for use in gene therapy trials. This paper provides a great example of discoveries in one field impacting another, and moving them both forward.

Nature Methods, February 7, 2010
CIRM funding: Michael Longaker (RL1-00662-1); (T1-00001)

DG,

Embryonic stem cells repair heart damage in mice

Researchers at the Stanford University School of Medicine found that cells derived from human embryonic stem cells could repair damage in a mouse model of heart attack. The researchers first looked at which genes were active at every stage between the human embryonic stem cells and early heart muscle cells. The cells they implanted mirrored the genes that are active in the hearts of 20 week old fetal mice. After injecting the cells into the heart of a mouse with an induced heart attack, they found that the cells incorporated into the heart and significantly improved the heart’s ability to pump blood. This work could lead to new stem cell-based therapies for repairing damaged heart tissue

PLoS ONE: October 22, 2008
CIRM funding: Joseph Wu (RS1-00322)

Related Information: Stanford Stem Cell Biology and Regenerative Medicine Institute, Wu bio

Human Embryonic Stem Cells Trigger Immune Reaction in Mice

Researchers at the Stanford University School of Medicine have found that human embryonic stem cells trigger an immune response much like organ rejection when transplanted into mice. In the past, researchers had thought that transplanted embryonic stem cells might not be rejected the way transplanted organs are. Testing this theory, the team found that after transplanting human embryonic stem cells into normal mice, those cells disappeared within seven to ten days. In mice without an immune system the cells survived and even multiplied. Drugs used to prevent organ rejection also successfully prevented normal mice from rejecting the transplanted stem cells. These results suggest that any therapy involving transplanted embryonic stem cells will also require a way of preventing people from rejecting those therapeutic cells.

Proceedings of the National Academy of Sciences: September 2, 2008
CIRM funding: Joseph Wu (RS1-00322)

Related Information: Press Release, Stanford Stem Cell Biology and Regenerative Medicine Institute, Wu bio