CAMBRIDGE, Mass. (September 8, 2005) - What exactly makes a stem cell a stem cell? The question may seem simplistic, but while we know a great deal of what stem cells can do, we don't yet understand the molecular processes that afford them such unique attributes.
Now, researchers at Whitehead Institute for Biomedical Research working with human embryonic stem cells have uncovered the process responsible for the single-most tantalizing characteristic of these cells: their ability to become just about any type of cell in the body, a trait known as pluripotency.
When a sperm cell fuses with an egg, the cell that results is called a zygote. The zygote proceeds to divide into additional cells through the normal process of cell division. After a few days, when there are about 40 to 150 cells (of a mammalian embryo), a central fluid-filled cavity develops and the embryo is referred to as a blastocyte.
At first, all of the cells in the developing embryo are (embryonic) stem cells, of a type referred to as totipotent, because they can develop (directly or indirectly) into any other type of cell, including other totipotent stem cells. But by the blastocyte stage, the stem cells have lost the ability to remain totipotent when they divide. Yet they can still become any of the other more than 200 types of possible mammalian cells. Stem cells at this stage are referred to as pluripotent.
Human pluripotent stem cells are assumed to have the greatest therapeutic potential, because they can develop into any type of body tissue, and because they can also be cultured indefinitely as independent cells.
By the time the embryo has developed into an adult, there remain many stem cells -- adult stem cells -- but all have lost their pluripotency, as far as we can tell. Such stem cells can develop into certain limited types of cells -- different kinds of blood cells, for example -- but that's all.
So one important question is: What causes a pluripotent cell in an embryo to lose that property and to head down a path toward a cell that makes up a specific type of tissue? And the other side of the question is just as important: What allows a cell cultured outside an embryo to remain pluripotent?
The answer depends entirely on which of the 25,000 or so genes (in the case of the human genome) are "expressed", that is, capable of directing the production of one or more proteins. Some genes are always expressed, because the proteins they are responsible for are needed for the proper function of any cell. But other genes are not expressed unless their proteins are needed at a given time. Some of the genes of this latter kind determine (among other things) the type of cell one has. A liver cell, for instance, is a liver cell because certain specific genes are expressed.
So it is to be expected that there must be genes which, when expressed, maintain the initial pluripotency of an embryonic stem cell. Prior to the latest research findings, it had been determined that in humans there are (at least) three such genes, which are named (along with their associated proteins) Oct4, Sox2, and Nanog. It was known that all of these proteins are necessary for pluripotency, because if any one of the genes is not expressed, pluripotency is lost. It was also known that the three proteins do not play a direct role in cell function, such as forming part of the internal machinery of the cell. Instead, they were known to be transcription factors, which affect the expression of other genes.
What remained unclear was how these proteins did their job. A transcription factor can either facilitate or inhibit the expression of a gene, and several transcription factors usually work together to do this, by binding to specific locations in the cell's DNA. The finding of the present research is that when the three genes are expressed and all three proteins are produced, then if the proteins bind together at specific places they can inhibit the expression of 353 other genes. And so, when any of these three genes is silenced, 353 other genes can be expressed. All of these genes are responsible for other transcription factors, which in turn affect many more genes in a large cascade effect. Eventually new proteins are produced which lead to the cell's loss of plutipotency and its differentiation into some more specific type of cell.
The interaction of genes in a living cell is a lot like a computer program. Starting from some particular initial state, a program, whether it's in a computer or a cell, takes "input" from outside. Then the program state, influenced by the relevant external inputs, transitions to another state in the next "clock cycle". Ultimately, what is to be determined, is the overall "state diagram" of the genome. That is, what combination of expressed genes and external influences lead to a new set of expressed genes, new transcription factors, and new cell behavior? What has been figured out so far is just the very earliest stage of the puzzle.
This is still just the beginning of learning what's going on. Yet to be determined is what first inhibits one of more of Oct4, Sox2, and Nanog from being expressed. Presumably it's something in the cell's environment. And beyond that, what determines the path that the cell will eventually take, towards becoming a blood cell rather than a neuron, for example?
The new results inevitably raise the question: Is there some way to make a cell dedifferentiate and allow all three genes to become expressed, so that the cell becomes pluripotent again? It can't be very easy at all, because as long as so many of the 25,000 genes in the genome are expressed that are silent in a pluripotent cell, the internal environment is very different. Will the genie go back in the bottle? On the other hand, the process of cloning via "somatic cell nuclear transfer", has precisely this effect of resetting the initial conditions simply by removing the nucleus of a fully differentiated cell (of skin, say) and inserting it into an egg cell whose own nucleus has been removed. Well, it's not quite that easy, but of course such cloning has been done.
- September 9, 2005 - Researchers discover key to human embryonic stem-cell potential
- September 11, 2005 - Researchers Discover Key To Human Embryonic Stem-cell Potential
- September 17, 2005 - Forever Young: Digging for the roots of stem cells
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