Tuesday, November 10, 2009

NEW CLUES TO WHY STEM CELLS STOP DIVIDING



Scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory have pieced together a mechanism that causes a type of human adult stem cell to permanently stop dividing after being exposed to ionizing radiation.

Their research can be used to help refine cancer treatments that utilize ionizing radiation, and may help inform future work to protect the health of astronauts on missions to deep space. It also sheds light on cellular senescence, a process in which cells permanently stop dividing that is linked to cancer and aging.

Specifically, Lab scientists zeroed in on the protein that triggers senescence in human mesenchymal stem cells. Found in the bone marrow of juveniles and adults, these stem cells are critical for maintaining and repairing tissues such as bone, cartilage, and muscle.

Like all stem cells, human mesenchymal stem cells have the ability to proliferate and differentiate into specialized cell types. They sometimes stop dividing when they’re damaged, however, which can contribute to the transformation of normal cells into cancer cells and is believed to play a role in the aging process.

Now scientists have a better understanding of how this breakdown occurs.

“We found that X-ray induced cellular senescence of human mesenchymal stem cells is a highly complex process that is mediated by a critical protein kinase called CK2,” says Daojing Wang of Berkeley Lab’s Life Sciences Division, the principal investigator of a study that is published in the October 15, 2009 issue of the journal Cancer Research.

There has been tremendous interest in utilizing human mesenchymal stem cells in regenerative medicine and disease therapy because they are relatively easy to work with and are much less controversial than human embryonic stem cells, Wang says. But few studies have looked at the consequences of exposing these cells to ionizing radiation, which is used in CT scans, cancer radiotherapy, and nuclear medicine, he adds.

To address this problem, Wang and colleagues exposed human mesenchymal stem cells in culture to X-ray radiation, then imaged the telltale changes in a cell’s shape and proteins that indicate senescence. They also used a technique called gene knockdown, in which the expression of a gene is reduced, to home in on the specific protein that triggers senescence.

Their search led them to a type of protein, called a kinase, which modifies other proteins by adding a phosphoryl group to them.

They found that a protein kinase called CK2 plays a key role in controlling the structural reorganization of a cell’s scaffolding after the cell is exposed to ionizing radiation. The scaffolding gives a cell its shape and helps it divide, among other functions. Structural changes in this cellular scaffolding are a defining characteristic of cellular senescence — and now the protein that sets these changes in motion has been identified.

Their work may help explain why radiation therapy can sometimes lead to unintended secondary bone cancers in a small minority of cancer patients years after the patients undergo treatment. It also offers the best glimpse yet into the highly coordinated mechanism that drives X-ray induced cellular senescence of human mesenchymal stem cells.

In a related study published earlier this year in the International Journal of Radiation Oncology*Biology*Physics, Wang and colleagues found that space radiation encountered by astronauts during space travel exerts more damaging effects on human mesenchymal stem cells than X-rays. They used radiation from iron-56 isotopes to mimic space radiation, and found that it perturbs key protein networks inside the cells.

“Much more work is needed to further understand the health risks associated with ionizing radiation in order to provide countermeasures. We will continue to investigate the fate of mesenchymal stem cells in response to ionizing radiation in the context of aging and cancer,” says Wang.

(Photo: LBNL)

Lawrence Berkeley National Laboratory

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