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Oak Ridge National Laboratory

The UCLA team was able to pinpoint an ideal set of ingredients for an animal-free culture process capable of handling embryonic stem cells on a single cell level for more precise processes. In conventional embryonic stem cell cultures, bovine-based serum is used as the base, and then human cells are cultured on top of mouse feeder cells. 


Discovery brings embryonic stem cells closer to mainstream medicine

by Leslie Trew Magraw
Jan 28, 2011


Related Links

Center for Cell Control: A NIH Nanomedicine Development CenterGeron Corporation’s Phase I Clinical Trial in Spinal Cord Imaging (Click the play buttons to watch the videos)Map: Adult & Embryonic Stem Cell Research Across the United States

What are stem cells?

Stem cells are important because they are unspecialized and have the ability to develop into many different cell types. In many tissues stem cells function as a sort of internal repair system in the body, dividing virtually without limit to renew other cells. When a stem cell divides, each new cell can either remain a stem cell or become another kind of cell with a more specialized purpose, such as a muscle cell or a brain cell.

What's the difference between embryonic and adult stem cells?

While each has pluses and minuses when it comes to their potential use for regenerative therapies, a key difference between adult and embryonic stem cells lies in the number and type of differentiated cell types they are able to become. Embryonic stem cells are pluripotent -- they can become any type of cell in the body -- while adult stem cells are thought to only be able to become different cell types of their tissue of origin.
Clinical-grade embryonic stem cells may be a step closer to becoming part of mainstream medicine, thanks to a team of researchers at UCLA.

The team was able to pinpoint an ideal set of ingredients for an animal-free culture medium capable of supporting the long-term regeneration and maintenance of human embryonic stem cells.

The UCLA researchers said the biggest selling point of their discovery is that it will allow scientists to handle embryonic stem cells on a single cell level so that they can perform more precise processes on the cells.

This system, called single-cell passaging, could play a key role in supplying large quantities of clinic-grade stem cells and eliminate a regulatory roadblock to future therapies.

“The ability to manipulate or handle one cell is critically important for some of the biotechnologies,” said Hideaki Tsutsui, a mechanical engineer and one of the lead authors of the study. Trying to “introduce new genes into the stem cell without being able to handle one cell makes the biotechnology process very inefficient,” he said.

“But,” Tsutsui said, “if you can culture cells individually, and expose all the chemical stimuli uniformly to the entire population, it would benefit the manufacturing of those clinically transplantable cells in the future.”

The milestone was a result of an unusual collaboration between university biologists and engineers who applied control theory – a theoretical framework prevalent in the engineering world – to embryonic stem cell culturing.

According to Hideaki Tsuitsui, the thinking-outside-the-box approach worked.

Developing cultures that can grow consistently, and then maintaining those stem cells without large-scale cell die-off, has been a major roadblock in the area of regenerative medicine.

But Tsutsui and his team at the Center for Cell Control, one of eight National Institutes of Health centers for nanomedicine, believe they have come up with a combination that will bring the promise of embryonic stem cells closer to clinical and commercial therapies. Their findings were published this week in the journal Nature Communications.

In conventional embryonic stem cell cultures, bovine-based serum is used as the base, and then human cells are cultured on top of mouse embryonic fibroblast feeder cells. But the problems associated with animal-based media can be overcome by using chemically defined ingredients, Tsutsui said.

“With animal sera or mouse feeder cells, the quality varies over different batches, so even if you buy the same product, one bottle of serum is different from the other one. So, your cell culture won’t be consistent,” Tsutsui said.

“Our system successfully removed those feeder cells as well as the serum component of the media so we can have a better understanding, chemically, of what’s going on in the cells,” Tsutsui said.

Animal-based media can also introduce pathogens that can contaminate the human cells, according to Dr. Eric Svensson, professor of medicine at the University of Chicago. He said that when you're talking about injecting these stem cells into human patients, it would be nearly impossible to purify away any animal components that could cause allergic reactions or infections.

“Most of the big pharma companies aren’t real excited about developing ES cells if they can’t get rid of all the animal components and do things in a defined way,” Svensson said.

In addition to removing the animal-based sera and mouse feeder cells that have led to inconsistencies and complications in conventional stem cell culturing – something that has been done before – the team went a step further to remove another major hurdle to clinic-readiness. And that is to allow scientists to handle embryonic stem cells on a single cell level.

“With conventional cultures, or even the commercially available feeder-free, serum-free cultures, you cannot disassociate those clusters into individual cells. Ours allows all that,” he said.

Tsutsui said that when cells are cultured as clusters in a petri dish – to develop specialized cells like neuron or muscle cells, for example -- some cells receive more of chemical signals contained in the culture than others. “The manufacturing process of those special cells is not uniform among the entire population,” he said.

As the cluster grows, scientists need to split the culture into multiple plates.

Tsutsui said the problem comes when scientists try to separate the clusters into individual cells. “The cells suffer from environmental stress and then die,” he said. “Only about 0.1 percent of the entire population will survive.”

The low survival rate among individualized cells that have been isolated from the cluster has been a major obstacle to allowing stem cell-based regenerative therapies to make the leap from the lab to the clinic – something the new study’s findings could help accelerate.

Svensson agreed that their method could have a significant impact on clinic-readiness. “When you plate cells out at that single cell density – when you dissociate the clusters into single cells – only a few survive and grow up," he said. "Their conditions will allow most of the cells to survive or to survive more robustly. You wouldn't lose so many.”

How far in the future are we talking? “Probably ten years from now,” Tsutsui said. “Safety is a major concern, and there are still many issues we have to solve first” before the technology becomes commercially available. 

Tsutsui said he knows of two clinical studies involving human embryonic stem cells that have been created using chemically defined stem cell cultures on volunteer patients to repair spinal cord injuries and restore diminished eyesight. Only time will tell what we can learn from their results, but the possibilities seem endless.