New type of human stem cell may be more easily manipulated

Researchers at Massachusetts General Hospital and Harvard Stem Cell Institute say cells should be more useful for research, future therapies

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BOSTON—The debate over the questionof 'are all stem cells alike?' usually focuses on the imputeddifferences between cells extracted from embryos and differentiatedcells where pluripotency has been induced. If work being done byresearchers at the Massachusetts General Hospital Center forRegenerative Medicine (MGH-CRM) and the Harvard Stem Cell Institutepans out, there is another difference that may make all thedifference.

What the researchers have achieved thusfar is development of a new type of human pluripotent stem cell thatcan be manipulated more readily than currently available stem celllines. As described in the June 4 edition of Cell Stem Cell,these new cells could be used to create better cellular models ofdisease processes and eventually may permit repair ofdisease-associated gene mutations.
"It has been fairly easy tomanipulate stem cells from mice, but this has not been the case forhuman stem cells," explains Dr. Niels Geijsen of MGH-CRM, who ledthe study. All human lines are difficult to manipulate; for example,genes cannot be added or removed, he says.

"We had previously found that thegrowth factors in which mouse stem cells are derived define whatthose cells can do, and now we've applied those findings to humanstem cells," Giejsen adds.

The first mammalian embryonic stemcells (ESCs) were derived from mice and have proven very useful forstudying gene function and the impact of changes to individual genes.But techniques used in these studies to introduce a different versionof a single gene or inactivate a particular gene were ineffective inhuman ESCs. In addition, human ESCs proliferate much more slowly thando cells derived from mice and grow in flat, two-dimensionalcolonies, while mouse ESCs form tight, three-dimensional colonies. Asa result, it is been extremely difficult to propagate human ESCs froma single cell, which prevents the creation of genetically manipulatedhuman embryonic stem cell lines.

In previous work, Geijsen and hiscolleagues demonstrated that the growth factor conditions under whichstem cells are maintained in culture play an important role indefining the cells' functional properties. Since the growth factorsappeared to make such a difference, the researchers tried to make amore useful human pluripotent cell using a new approach. They derivedhuman induced pluripotent stem cells (iPSCs) in cultures containingthe growth factor LIF (leukemia inhibitory factor), which is used inthe creation of mouse ESCs, rather than the bFGF (basic fibroblastgrowth factor) routinely used with human ESCs.

These cells, which are created byreprogramming adult cells and have many of the characteristics ofhuman ECSs, including resistance to manipulation, visibly resembledmouse ESCs and proved amenable to a standard gene manipulationtechnique that exchanges matching sequences of DNA, allowing thetargeted deactivation or correction of a specific gene. The abilityto manipulate these new cells depended on both the continued presenceof LIF and expression of the five genes that are used inreprogramming adult cells into iPSCs. If any of those factors wasremoved, these hLR5- (for human LIF and five reprogramming factors)iPSCs reverted to standard iPSCs.
The cells are "metastable," Geijsennotes, and upon ectopic factor withdrawal, they revert to standardhuman iPSCs.

"Genetic changes introduced intohLR5-iPSCs would be retained when they are converted back to iPSCs,which we then can use to generate cell lines for future research,drug development and someday stem-cell based gene-correctiontherapies," says Geijsen.
An assistant professor of medicine atHarvard Medical School and a principal faculty member of the HarvardStem Cell Institute, Geijsen says his next step will be to apply thisnew technique to develop specific stem cell lines using neurons frompatients with ALS or spinal muscular atrophy (SMA), a disease that isoften fatal during infancy. In addition, he foresees assistingpartners to develop targeted mutations of interest in their research.

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