Stem cell probe targets pluripotency

UC SANTA BARBARA (US) — Pluripotency—the ability of human embryonic stem cells to differentiate or become almost any cell in the body—is emerging as an important concept in understanding how stem cell biology works.

“The beauty and elegance of stem cells is that they have these dual properties,” says Kenneth Kosik, professor of molecular, cellular, and development biology at the University of California, Santa Barbara.

“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” including pluripotent cells.

“The big engines of change are the transcription factors,” he explains. “They drive the laboratory procedure by which we can reverse the progression during development from stem cell to differentiated cell and use differentiated cells from our skin to make stem cells.”

With human embryonic stem cells, researchers for some time 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.”

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When several hundred members of a class of molecules called microRNAs are measured it becomes possible to distinguish different cell types including the discovery that stem cells fall into two broad categories. (Credit: Pierre Neveu)

It doesn’t matter how scientists make or obtain stem cells for research, Kosik says.

They can be bona fide human embryonic stem cells (HESC) or induced pluripotent stem cells (IPSC) induced from a skin cell. The microRNA patterns don’t “respect” how the cells were made.

In the current study, published in the journal Cell Stem Cell, the researchers found that all pluripotent stem cells are not identical, but did not differ by how they originated. The scientists found two groups of stem cells, irrespective of origin.

When looking at microRNA, the overall profile is an extraordinarily good predictor—maybe the best available—of what type of cell you have.

“You could be looking through the microscope at a tumor, and you may not be sure about that tumor,” Kosik says. “Maybe the tumor is in the brain, but you don’t know whether it is a brain tumor, or a metastasis from somewhere else. You can’t always tell exactly what type of cells they are. The microRNAs will tell you.

“Those profiles can tell you the different types of cancer; they can tell you the different types of cells; they can distinguish stem cells from other cells; and they can distinguish skin cells from brain cells.

“Those profiles, when you look at them in their totality, offer a unique signature that can inform you as to what type of cell you have. So that’s a very important property of these microRNAs.”

The scientists looked at 400 different microRNAs in both embryonic and induced pluripotent cells. Humans have approximately 1,000 microRNAs.

Pluripotent stem cells have some similarity to cancer cells: they’re immortal, they self-renew, and they keep dividing.

“That’s their property, self-renewal, proliferation,” says Kosik. “And that’s what cancer does. How can it be that pluripotent stem cells can self-renew and are not cancer, but cancer cells self-renew and are cancer? Cancer lacks any control over itself. What’s the difference?”

The scientists included studies of 40 types of differentiated body cells, in
the microRNA testing. Not surprisingly, they found that the microRNA was very different in the cancer cells and the differentiated cells.

The surprise was that when looking at pluripotent cells, some are more similar to cancer and others are less.

“One of the big problems that people worry about in the use of stem cells for the repair of body parts, is whether or not you are going to be creating cancer,” says Kosik. “That’s a big worry—one of the major worries.

“So if we have a way here, and this we don’t know yet, but if these microRNA profiles that look like cancer indicate a propensity toward cancer, then that would be very nice to know. But we don’t know that yet.”

Kosik says if doctors are going to use stem cells for body repairs, they don’t want them to be cancerous, but they do want them to have enough growth potential that they will really make a difference.

“So maybe they should look a little bit like cancer. On the other hand, you don’t want them to become a tumor. So maybe you want them to look a little less like cancer. At this point you could make either argument. We just don’t know.”

Researchers from University of California, Los Angeles, Harvard University, and Yale University contributed to the study.

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