One of the most exciting frontiers in medicine is the potential use of embryonic stem cells (ES cells) for treating a host of congenital, developmental, or degenerative diseases. Cell replacement strategies are particularly relevant for tissues and organs that have little capacity for self-repair.
ES cells possess two properties that make them especially well suited for cell therapy. First, they retain the flexibility to become any one of the more than 200 cell types that make up the human body. Given the right combination of signals, ES cells develop into mature cells that can function as neurons, muscle, bone, blood or other cell types. Stem cells with such flexibility are described as "pluripotent," to indicate their high potential to differentiate into a wide variety of cell types.
A second feature of embryonic stem cells is their ability to remain in an undifferentiated state and to divide indefinitely. This property of "self-renewal" means that virtually unlimited numbers of well-defined, genetically characterized cells can be produced in culture.
Stem cells are unspecialized cells that have the capability of renewing themselves through cell division. Stem cells also have the potential to become different cell types depending on the signals they receive from their environment.
Not all stem cells have the same capacity to generate different cell types. A fertilized egg, or zygote, is said to be "totipotent," that is, it has the ability to give rise to every cell type in the entire body, as well as the placenta. Other stem cells are "pluripotent" and have the ability to develop into every cell type in the body, but lack the ability to give rise to extraembryonic tissue, such as the placenta. Still others are more restricted in the type of cells they can become, and are said to be multipotent.
Embryonic stem cells, or ES cells, are pluripotent stem cells derived from embryos generated by in vitro fertilization (IVF).
Following fertilization, the egg divides first into two cells, then into four. With more divisions, a multicellular ball of cells known as a blastocyst is formed.
The blastocyst is a hollow ball made up of two cell layers: an outer layer, called the trophoblast, eventually forms the placenta, and an inner cluster of cells, known as the inner cell mass, becomes the embryo.
At this stage, the inner cell mass is made up of embryonic stem cells. It is possible to extract these embryonic stem cells with a pipette and culture them in the laboratory.
Under appropriate culture conditions, these embryonic stem cells divide or "self-renew," and the cell mass grows. The ability of embryonic stem cells to self-renew indefinitely while retaining their undifferentiated, pluripotent state is a key feature of these cells. Cells from a single Petri dish can be used to seed many other Petri dishes. In this way, unlimited numbers of undifferentiated, pluripotent stem cells can be produced and maintained.
If appropriate signaling molecules are provided, ES cells can be coaxed into becoming many different mature cell types. Groups of cells may develop properties of bone cells, or of pancreatic cells. Others resemble muscle cells that can contract, and still others acquire the characteristics of nerve cells.
By generating large numbers of differentiated cells from ES cells, scientists hope to replace cells in the body that have been lost or damaged by injury or disease. However, because ES cells generated from IVF blastocysts will have a different genetic background from that of the recipient, the grafted cells may be rejected. It would therefore be desirable to transplant ES cells that are a genetic match to the recipient.
Until recently, it was not possible to induce a fully mature cell from an adult animal to become another cell type. However, this hurdle has now been overcome.
Shinya Yamanaka found that by inserting four specific genes into adult cells, the cells will revert to an embryonic, pluripotent state. One technique uses viral vectors to insert these genes into adult skin cells. The cells carrying the vector are selected and expanded in culture.
Cells generated in this way are referred to as induced pluripotent stem cells, or iPS cells. Like ES cells generated from blastocysts, iPS cells can self-renew, and can also be induced to differentiate into specialized cells.
Because the iPS cells can be made directly from the cells of a patient, an immune response may be avoided. The technique also does not require the destruction of a human embryo in order to derive pluripotent stem cells.
Stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth. Human ES cells were first isolated and cultured in 1998 by James Thomson at the University of Wisconsin. Since then, numerous laboratories have been actively engaged in identifying the optimal conditions for regulating stem cell behavior and activity. Researchers have also identified conditions that allow some specialized adult cells to be "reprogrammed" to assume a stem cell-like state.
Although the transplantation of mature cells derived from ES cells offers hope for the treatment of many diseases, obstacles to this therapy remain. One side effect that worries most researchers is the ability of undifferentiated stem cells to grow unchecked and produce tumors. Because pluripotency and self-renewal are two key features of embryonic stem cells, they can develop growths known as teratomas that bear cells of ectodermal, mesodermal, and endodermal origins. Researchers reason that if they separate the undifferentiated embryonic stem cells from their differentiated progeny, and only transplant the differentiated cells needed by the patient, it will be possible to treat the disease without the fear of tumor formation.
Stem cells have other applications in addition to producing cells for transplantation therapies. Human stem cells can serve as model systems for understanding the biology of human development, and consequently diseases that arise from faulty development. Cells derived from human stem cells can also be used for drug discovery and for testing the toxicity of different drugs and compounds. Because these are human cells, they bear human receptors and signaling and metabolic pathways. They are therefore more suitable as test models than cells derived from animals, and will provide more reliable information regarding toxicity, dosage, and metabolism of drugs that are ultimately intended for human patients.