BioWorld International Correspondent

LONDON - The day when researchers can take someone's skin or blood cells and turn them back into undifferentiated stem cells that could be used to treat heart disease or neurological disorders has come a step closer.

A study in the UK has provided new insight into the mechanisms by which an oocyte can reprogram the nucleus of an adult cell. The work, by Stina Simonsson and John Gurdon, both of the University of Cambridge, shows that such reprogramming can happen only if methyl groups covering DNA are stripped away.

Gurdon, professor of cell biology, told BioWorld International: "We have shown that DNA demethylation is a necessary step for the reprogramming or rejuvenation of adult cells back to the stage where they express the same genes that are expressed in stem cells. This is one of the very few pieces of work that has begun to throw light on the mechanism of rejuvenation."

The study is reported in the Sept. 27, 2004, issue of Nature Cell Biology, in a paper titled "DNA methylation is necessary for the epigenetic reprogramming of somatic cell nuclei."

Very little work so far has been devoted to investigating ways in which differentiated body cells can be made to revert to the pluripotential stem cell state. If it were possible to reverse the cellular-aging process in that way, then it would be theoretically possible - with the help of various growth factors - to encourage cells that had regained their "youth" in that way to differentiate into whatever kind of tissue a person needed.

They might, for example, need a fresh supply of heart muscle cells to replenish failing ones. Or they might need cells to correct a neurological disease, such as Parkinson's or Huntingdon's.

Such treatment would have the advantage in that no immunosuppression would be needed to allow the cells to survive: Because the cells would be the patient's own, they would not be rejected by the immune system.

One of the first steps along the path toward that goal is to understand how gene expression differs in stem cells compared to differentiated cells.

Researchers have known for some time that when the nucleus from a differentiated cell, such as a skin cell or a blood cell, is inserted into an oocyte, something in the cytoplasm causes the pattern of gene expression by the nucleus to change. Simonsson and Gurdon decided to investigate that process further.

They worked with oocytes from the frog Xenopus, because they are large and easily obtained. The cells also respond to DNA from human or murine cells as human oocytes would.

The pair injected nuclei from murine thymus cells into Xenopus oocytes. They found that the nuclei soon began to express a gene that normally is switched on only in early embryos and stem cells. That gene encodes a transcription factor called oct4.

Expression of oct4 is crucial if a cell is to remain an embryonic stem cell, and continue to divide to form more embryonic stem cells. Once oct4 expression is turned off, the cell differentiates.

Simonsson and Gurdon carried out experiments that showed that oct4 had that effect by demethylating the DNA in the nucleus. Gurdon said: "We found that an important step in changing the pattern of DNA expression back to an embryonic state was demethylation of DNA. The normal function of the methyl groups is to switch genes off, and cells use methylation of DNA as a way of keeping genes off, as they become more specialized."

Little is known about how oct4 brings about demethylation. Gurdon said: "Our next step will be to try to find out about the molecules and mechanisms by which this rejuvenation-like process happens. If scientists can find these molecules they could use them to begin to reprogram or rejuvenate adult human cells directly."

No Comments