Stem Cells 101: What they are, how they work
Stem cells are currently at the core of a great deal of scientific research – and debate. But what scientists know is that stem cells are not a single entity – they encompass a broad range of cell types, taken from different times and places in the body. To understand where the term arose, we need to think about how the human body maintains itself into old age.
Cells in the body simply don’t last as long as old people do, and must be continuously replaced. In each tissue of the body, the rate of death and replacement (turnover) of cells is different. The cells lining our intestines, of which there are millions, turn over after only a few days. Red blood cells last more than one hundred days, and so turn over more slowly. Brain cells last a very long time, and some may never be replaced.
The Basics are the Same
Despite these differences in timing, the basic mechanism of turnover is thought to be the same for all tissues. Each contains a small population of “stem cells” with special properties. First, they have the ability to differentiate into all the cell types found in that particular tissue – all the cell types found in the blood, or the epidermis of the skin, for example. Second, they divide very slowly. Third, their divisions are asymmetric, so that after each division, one daughter cell remains a stem cell. The other loses these properties, but retains the ability to divide, thus amplifying the population of differentiating cells. These daughter cells are known as “transit amplifying” cells. After a set number of divisions, they stop dividing and undergo terminal differentiation to form the mature cell types of the tissue.
What Drives Asymmetry
Stem cell asymmetry is maintained by specific proteins localized in different regions of the stem cell, so they are differentially inherited by the two daughter cells. This asymmetric division is essential to preserving the stem cell population. If cell division were equal, so that both daughters became transit amplifying cells, then the body would immediately run out of stem cells.
Asymmetry of the stem cells is generated and maintained by signals that pass between the stem cells and the specialized cells that lie next to them called “niche” cells. During embryogenesis, stem cells and niche cells join together to form a life-long partnership that will maintain the specific tissue concerned. In most tissues, the mechanism by which this partnership is established and maintained is still poorly understood.
Where It All Begins
Where do these stem cells and niche cells come from? All cells arise in the early embryo from a group of a few dozen cells (the “inner cell mass”) surrounded by a shell of cells (the “trophoblast”) that later forms the placenta. When early embryos at this stage are placed into culture under appropriate conditions, the inner cell mass cells give rise to a dividing population of cells, whose totipotency is preserved through many cell cycles. Individual cells from these cultures can be selected and grown as lines of genetically identical cells. These cell lines were named “embryonic stem cells” or ES cell lines. Since they do not divide asymmetrically, and are unrestricted in the cell types they can form, they are not the same as the tissue stem cells described earlier. To keep them separate, they are sometimes defined as adult stem cells (AS cells) and embryonic stem cells (ES cells) respectively, because their uses raise different technical and ethical issues.
Germ Cells – Precursors to Stem Cells
To complicate things still further, other cell types can behave like ES cells when cultured under specific conditions. Primordial germ cells in the early embryo are the founder cells of all the gametes (and thus all the future progeny of that embryo) that form during its life. Although the germ cells differentiate in the gonads, they do not arise there. Instead, they arise at an earlier stage in the embryo, and migrate through the tissues of the embryo until they find the gonads (more about this in the article "Where it All Begins"), where they colonize and start their differentiation.
Analysis of a number of mammalian species has shown that during the migration of germ cells, and at an early phase of their differentiation, a culture of the cells can generate apparently totipotent populations of cells with properties similar to ES cells. Hematopoietic stem cells also migrate, and can be found at very low concentration in the circulating blood. In particular, blood from the umbilical cord at birth, which contains a reservoir of fetal blood that was circulating between the fetus and its placenta before birth, will also generate pluripotential cells when cultured under specific conditions.
The Need for Further Exploration
Although “stem cells” is an elastic term applied to different cell types, the distinctions are important. Deriving lines of ES cells requires the culture of a human embryo, which raises ethical issues that are the subject of ongoing debate. AS cells are less contentious, because they can theoretically be isolated and cultured directly from a patient, but have other limitations.
In a recent additional twist, the progression from stem cell to differentiated cell has been found to be reversible. By introducing a specific selection of genes normally expressed by ES cells into adult cells in culture, reversion to a stem cell-like state has been achieved.
The landscape of science is ever-changing, and new discoveries with and about stem cells will continue to alter that landscape. Because their normal function is to “generate” the tissues of the body, stem cells can theoretically be used to “re-generate” tissues lost by disease, congenital malformation, or trauma, and thus offer significant potential for therapeutics. Continued basic and translational research, and public debate, will be required as our understanding of the use of stem cells in disease research and therapy matures.
