January 29, 2005
Technique Speeds Search For Methods To Change Cell Types

Some UC San Diego researchers have developed a process to help automate the search for compounds that will turn less differentiated stem cells into more differentiated specialized cell types.

Bioengineering researchers at the University of California, San Diego have invented a process to help turn embryonic stem cells into the types of specialized cells being sought as possible treatments for dozens of human diseases and health conditions. Sangeeta Bhatia and Shu Chien, UCSD bioengineering professors, and Christopher J. Flaim, a bioengineering graduate student, described the cell-culture technique in a paper published in the February issue of Nature Methods, which became available online on Jan. 21.

It is very likely this technique would be useful in testing proteins for their ability to turn non-embryonic stem cells into other cell types as well.

To find out what would work they had to develop the means to automatically test many different combinations and concentrations of proteins.

“We kept the other factors constant and developed a miniaturized technique to precisely vary extracellular matrix proteins as a way to identify which combinations were optimal in producing differentiated cells from stem cells,” said Bhatia. She, Chien, and Flaim described in their paper a technique that enabled them to identify the precise mix of proteins that optimally prompted mouse embryonic stem cells to begin the differentiation process into liver cells. Bhatia, Chien, and Flaim designed the technique with other cell biologists in mind so that any of them could duplicate it with off-the-shelf chemicals and standardized laboratory machinery. “We think other researchers could easily use this technique with any other tissue in mouse, or human, or any other species,” said Bhatia.

They adopted an existing machine that delivers tiny volumes of DNA and made it deliver protein instead.

In their experiments, the UCSD researchers took advantage of the knowledge that the extracellular matrix in liver is comprised primarily of just five proteins. They applied spots of all 32 possible combinations of the five proteins as engineered niches onto the surface of gel-coated slides, and then added mouse embryonic stem cells to the niches. After the cells were allowed to grow, the researchers assayed their progression into liver cells. “We looked at all the combinations at once,” said Bhatia. “Nobody has done this combinatorial approach before.”

Bhatia, Chien, and Flaim reported that either collagen-1 or fibronectin had strongly positive effects on the differentiation of the stem cells they tested. Unexpectedly however, when both collagen-1 and fibronectin were combined in one niche, the liver cell differentiation process was subtly inhibited. “You would not predict that from the customary cell biology experiments,” said Bhatia. “By using this combinatorial technique we were surprised to find many interesting interactions, and we were able to tease out the effects of each protein, alone and in combination with others.”

Cell biologists have not performed such combinatorial assays for other desired cell types because they had no practical way to do so. Bhatia, Chien, and Flaim seized on the unique ability of so-called DNA spotting machines to deliver tiny volumes of liquid, about one trillionth of a liter per spot. The spotting machines, which cost about $20,000, have become common fixtures at most research universities, but the innovation reported today in Nature Methods involved using such a machine to spot solutions of proteins rather than DNA. The UCSD researchers also refined other parameters so that the technique would be reproducible in other research laboratories.

The more important story here is not the discovery of particular protein combinations that make stem cells differentiate into liver cells. What will be more valuable in the longer run is the ability to apply their technique to more combinations of proteins to convert embryonic and other cell types into various desired cell types. With better tools the rate of progress can accelerate by orders of magnitude. This is yet another example of the general trend toward the development of techniques that are accelerating the rate of advance of biomedical research.

Share |      Randall Parker, 2005 January 29 11:44 PM  Biotech Organ Replacement


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