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Tweaking the levels of factors used during the reprogramming of adult cells into induced pluriopotent stem (iPS) cells greatly affects the quality of the resulting iPS cells, according to Whitehead Institute researchers.

“This conclusion is something that I think is very surprising or unexpected—that the levels of these reprogramming factors determine the quality of the iPS cells,” says Whitehead Founding Member Rudolf Jaenisch. “We never thought they’d make a difference, but they do.”

An article describing this work is published in the December 2 issue of Cell Stem Cell.

“This conclusion is something that I think is very surprising or unexpected—that the levels of these reprogramming factors determine the quality of the iPS cells,” says Whitehead Founding Member Rudolf Jaenisch. “We never thought they’d make a difference, but they do.”

iPS cells are made by introducing specific reprogramming genes into adult cells. These factors push the cells into a pluripotent state similar to that of embryonic stem (ES) cells. Like ES cells, iPS cells can become any cell type in the body, a characteristic that could make them well-suited for therapeutic cell transplantation or for creating cell lines to study such diseases as Parkinson’s and Alzheimer’s.

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By irradiating typical polystyrene lab plates with ultraviolet (UV) waves, Whitehead Institute and MIT scientists have created a surface capable of tripling the number of human embryonic stem (ES) and induced pluripotent stem (iPS) cells that can be grown in culture by current methods. Use of this novel surface also eliminates the need for layers of mouse “feeder cells” to support ES- and iPS-cell growth.

“Polystyrene is the most common cell culture surface used in labs, and to be able to do a simple treatment and get something that works better than the mouse feeder layers is great and potentially has a lot of utility,” says Daniel Anderson, Associate Professor in the Harvard-MIT Division of Health Sciences & Technology.

The research is published online this week in the Proceedings of the National Academy of Sciences (PNAS).

“I think it’s going to be a useful technique,” says Krishanu Saha, a postdoctoral researcher in Whitehead Member Rudolf Jaenisch’s lab. “There is a lot of push, at least in the field, to [eliminate animal products]. If you were one day to inject these cells into patients, you wouldn’t have to worry about as many safety risks as if you had co-cultured them with animal cells.”

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Whitehead Institute researchers have developed a novel method of removing potential cancer-causing genes during the reprogramming of skin cells from Parkinson’s disease patients into an embryonic-stem-cell-like state. Scientists were then able to use the resulting induced pluripotent stem (iPS) cells to derive dopamine-producing neurons, the cell type that degenerates in Parkinson’s disease patients.

The work marks the first time researchers have generated human iPS cells that have maintained their embryonic stem-cell-like properties after the removal of reprogramming genes. The findings are published in the March 6 edition of the journal Cell.

Removing the reprogramming genes is also important because of those genes’ effect on an iPS cell‘s gene expression (a measure of which genes the cell is using and how much it’s using those genes). When the researchers compared the gene expressions of human embryonic stem cells to iPS cells with and without the reprogramming factors, iPS cells without the reprogramming genes had a gene expression closer to human embryonic stem cells than to the same iPS cells that still contained the reprogramming genes.

“The reprogramming factors are known to bind to and affect the expression of 3,000 genes in the entire genome, so having artificial expression of those genes will change the cell’s overall gene expression,” Dirk Hockemeyer, who is also a co-author of the Cell article. “That’s why the four reprogramming genes can mess up the system so much. From now on, it will be tough for researchers to leave the reprogramming genes in iPS cells.”

from http://web.mit.edu/newsoffice/2009/parkinsons-stem-0305.html

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Using two distinct methods, Whitehead Institute researchers have successfully and consistently manipulated targeted genes in both human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells (adult cells that have been reprogrammed to an embryonic stem cell-like state).

In one case, scientists employed proteins known as zinc finger nucleases (ZFNs) to change a single base pair in the genome, allowing them either to insert or remove mutations known to cause early-onset Parkinson’s disease (PD). The second method relies on proteins called transcription activator like effector nucleases (TALENs) capable of altering specific genes with similar efficiency and precision as ZFNs. Both sets of experiments were conducted in close collaboration with scientists at Sangamo BioSciences.

Targeted genetic manipulation addresses a problem that has been plaguing human stem cell research – the ability to cleanly and site-specifically modify the genomes of human ES and iPS cells. Realizing the therapeutic promise of these cells depends on such changes to fix disease-causing mutations before the cells could be transplanted into patients or to create cell lines that researchers can use to study genetic diseases.

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