Scientists shed light on inner workings of human embryonic stem cells

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Scientists shed light on inner workings of human embryonic stem cells

http://www.eurekalert.org/pub_releases/2009-04/uoc--ssl043009.php

IMAGES at link: S. Kosik is a professor in the department of molecular,

cellular & developmental biology. Kosik is also co-director and Harriman Chair

in Neuroscience Research of UCSB's Neuroscience Research Institute..

(Santa Barbara, Calif.) –– Scientists at UC Santa Barbara have made a

significant discovery in understanding the way human embryonic stem cells

function.

They explain nature's way of controlling whether these cells will renew, or will

transform to become part of an ear, a liver, or any other part of the human

body. The study is reported in the May 1 issue of the journal Cell.

The scientists say the finding bodes well for cancer research, since tumor stem

cells are the engines responsible for the growth of tumors. The discovery is

also expected to help with other diseases and injuries. The study describes

nature's negative feedback loop in cell biology.

" We have found an element in the cell that controls 'pluripotency,' that is the

ability of the human embryonic stem cell to differentiate or become almost any

cell in the body, " said senior author S. Kosik, professor in the

Department of Molecular, Cellular & Developmental Biology. Kosik is also

co-director and Harriman Chair in Neuroscience Research of UCSB's Neuroscience

Research Institute.

" The beauty and elegance of stem cells is that they have these dual properties, "

said Kosik. " On the one hand, they can proliferate –– they can divide and renew.

On the other hand, they can also transform themselves into any tissue in the

body, any type of cell in the body. "

The research team includes Thomson, who provided an important proof to the

research effort. Thomson, an adjunct professor at UCSB, is considered the

" father of stem cell biology. " Thomson pioneered work in the isolation and

culture of non-human primate and human embryonic stem cells. These cells provide

researchers with unprecedented access to the cellular components of the human

body, with applications in basic research, drug discovery, and transplantation

medicine.

With regard to human embryonic stem cells, Kosik explained that for some time he

and his team have been studying a set of control genes called microRNAs. " To

really understand microRNAs, the first step is to remember the central dogma of

biology ––DNA is the template for RNA and RNA is translated to protein. But

microRNAs stop at the RNA step and never go on to make a protein.

" The heart of the matter is that before this paper, we knew that if you want to

maintain a pluripotent state and allow self-renewal of embryonic stem cells, you

have to sustain levels of transcription factors, " said Kosik. " We also knew that

stem cells transition to a differentiated state when you decrease those factors.

Now we know how that happens a little better. "

The new research shows that a microRNA –– a single-stranded RNA whose function

is to decrease gene expression –– lowers the activity of three key ingredients

in the recipe for embryonic stem cells. This microRNA is known as miR-145. The

discovery may have implications for improving the efficiency of methods designed

to reprogram differentiated cells into embryonic stem cell-like cells.

As few as three or four genes can make cells pluripotent. " We know what these

genes are, " Kosik said. That information was used recently for one of the most

astounding breakthroughs of biology of the last couple of years –– the discovery

of induced pluripotent skin cells.

" You can take a cell, a skin cell, or possibly any cell of the body, and revert

it back to a stem cell, " Kosik said. " The way it's done, is that you take the

transcription factors that are required for the pluripotent state, and you get

them to express themselves in the skin cells; that's how you can restore the

embryonic stem cell state. You clone a gene, you put it into what's called a

vector, which means you put it into a little bit of housing that allows those

genes to get into a cell, then you shoot them into a stem cell. Next, when those

genes –– those very critical pluripotent cell genes –– get turned on, the skin

cell starts to change, it goes back to the embryonic pluripotent stem cell

state. "

The researchers explained that a rise in miR-145 prevents human embryonic stem

cells' self-renewal and lowers the activity of genes that lend stem cells the

capacity to produce other cell types. It also sends the cells on a path toward

differentiation. In contrast, when miR-145 is lost, the embryonic stem cells are

prevented from differentiating as the concentrations of transcription factors

rise.

They also show that the control between miR-145 and the " reprogramming factors "

goes both ways. The promoter for miR-145 is bound and repressed by a

transcription factor known as OCT4, they found.

" It's a beautiful double negative feedback loop, " Kosik said. " They control each

other. That is the essence of this work. "

Because there is typically less " wiggle room " in the levels of microRNA compared

to mRNA, further studies are needed to quantify more precisely the copy numbers

of miR-145 and its targets, to figure out exactly how this layer of control

really works, Kosik said.

Kosik credits the lion's share of this discovery to first author Na Xu, a

postdoctoral fellow who is also supported by the California Institute for

Regenerative Medicine (CIRM). " Na Xu deserves enormous credit for this work, "

said Kosik. " She performed nearly every experiment in the paper and was the

major contributor to the ideas in the paper. " Meanwhile, Thales

Papagiannakopoulos, a graduate student working in the Kosik lab, was very

generous in helping Na Xu with one of the experiments. He helped with one of

several proofs that showed that the targets of miR-145 are the three

transcription factors that are being reported, explained Kosik.

Thomson provided one of several proofs for the control point of miR-145

expression, said Kosik.