Extreme makeover: Stanford scientists explore new way to change cell's identity

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Extreme makeover: Stanford scientists explore new way to change cell's identity

http://www.eurekalert.org/pub_releases/2009-05/sumc-ems050509.php

STANFORD, Calif. — Even cells aren't immune to peer pressure. Scientists at the

Stanford University School of Medicine have now shown that skin cells can be

coaxed to behave like muscle cells — and muscle cells like skin cells — solely

by altering who they hang out with: the relative levels of the ingredients

inside the cell.

The fickleness of the cells, and the relative ease with which they make the

switch, provide a glimpse into the genetic reprogramming that must occur for a

cell to become something it's not.

" We'd all like to understand what happens inside the black box, " said Helen

Blau, PhD, the E. and Delia B. Baxter Professor and member of Stanford's

Stem Cell Biology and Regenerative Medicine Institute. " These types of

experiments will help us to identify the earliest regulators of reprogramming. "

Harnessing these genetic makeovers will allow scientists to better understand

how to induce specialized adult cells to revert to a stem-cell-like state in a

process called induced pluripotency. These newly pluripotent, or iPS, cells,

which can then be encouraged to branch out into a variety of other cell types,

have shown increasing promise as possible therapies for disorders like diabetes.

But Blau's experiments suggest an intriguing alternative to iPS: that of

enticing specialized adult cells to move sideways from one developmental fate to

another without requiring a dip into the stem cell pool.

Blau, who directs the Baxter Laboratory of Genetic Pharmacology at the medical

school, is the senior author of the research, which is published in the May

issue of the FASEB Journal. She and her laboratory members fused mouse muscle

cells with human skin cells to create hybrids called heterokaryons. In

heterokaryons, the nuclei of each cell type remains distinct, and the influence

of one on the nature of the other can be clearly distinguished. They then

examined the hybrids to see if they began to look and act more like muscle

cells, skin cells or something in between.

The researchers use species-specific differences to track the unique

gene-expression profiles of each cell type. They found that if the muscle cell

nuclei outnumbered the skin cell nuclei, the skin nuclei began to express

muscle-specific genes within a few hours of fusion. When the skin cell nuclei

were more numerous, the muscle cell nuclei switched to express skin-specific

genes. What's more, the heterokaryons themselves assumed the morphology of the

ruling cell type — flat and roundish like skin cells or long and skinny like

muscle cells.

" We were especially pleased to see that the muscle cells could begin to act like

skin, " said Blau, whose laboratory had previously shown in similar experiments

that muscle cells can influence the fate of other cells. " But now we know it can

go both ways. "

The outnumbered nuclei assumed their new identities both quickly and decisively

— there was a telling lack of cells expressing characteristics of both muscle

and skin.

" It's all or nothing, " said Blau. " At a certain threshold, a switch is flipped

and the cell becomes committed to a specific fate. " Although the precise

molecular regulators of such a switch have not yet been identified, Blau

speculates that proteins or small RNAs in the cytoplasm of the predominant cell

modify the gene expression program of the minority nuclei.

In addition to homing in on these regulators, the researchers are repeating the

experiment with a variety of different cell types. " This shows that it can be

done, " said Blau. " Currently, inducing pluripotency in adult cells is time

consuming and inefficient. We'd like to improve on that, or explore ways to skip

that step altogether. We're coming at the problem from all angles. "

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Other Stanford researchers involved in the study include Adam Palermo, PhD,

currently at Genzyme Corp.; Regis Doyonnas, PhD, currently at Pfizer, Inc.;

research associate Nidhi Bhutani, PhD; Pomerantz, MD, currently an

assistant professor at the University of California - San Francisco; and Ozan

Alkan, PhD, currently at the Broad Institute at the Massachusetts Institute of

Technology. The research was supported by the National Science Foundation, the

National Institutes of Health and the Baxter Foundation.