The Ultimate Stem Cells

Tissue engineering is based on the hypothesis that fully differentiated adult cells cannot reproduce to replace lost tissue, but quiescent stem cells must be called into action if repair is to occur. The cloning of sheep followed by similar successes with mice, cows, goats, and pigs has caused the scientific world to rethink this long-standing biological axiom. In each instance, the DNA of an adult cell was transferred to an egg cell whose own nucleus had been removed. The result was a reprogramming of the adult DNA so that the entire genome was unleashed and able to reproduce a complete organism, identical to the donor of the adult cell. The possibilities that ow from this accomplishment, both practical and theoretical, are enormous.

The most immediate applications point to reproducing herds of the choicest livestock, or the introduction of specific genes so that cloned animals can produce useful medicines in their milk. The latter operation has already been accomplished with the embryonic fibroblast as the DNA donor rather than a differentiated adult cell. In this example, sheep were engineered to produce the blood-clotting protein factor IX in their milk. Another potential application is the introduction of genes that result in cloned animals that have organs compatible for human transplantation.

Even more intriguing to the bio-engineer is the revelation that adult cells are not irreversibly committed to a single destiny, but depending on the environmental conditions, can be enticed to revert to the genetic potential of the fertilized egg. Someday it may be possible to control the level of reprogramming so that a mature cell can be restricted to forming specific tissues. Such technology would be a way of producing tissues that are genetically identical to those of the patient and not subject to rejection. Researchers in the private sector have already developed ways to manipulate adult bone marrow stromal cells in culture so that they can be directed to become bone, cartilage, or fat.

A related advance was the discovery of human embryonic stem cells. These cells, which make up the cell mass of the very early embryo, cannot form complete organisms, but retain the ability to differentiate into all of the cell types found in the adult body. In mice, these embryonic stem (ES) cells have been cloned and used to generate mouse models of human genetic diseases and abnormalities. The isolation of human ES cells also opens up the possibility of growing replacement human cells and tissues.

Cells isolated from early embryos can be grown indefinitely in culture, remain undifferentiated, yet retain the ability to form tissues derived from all three embryonic germ layers -- ectoderm, endoderm, and mesoderm. The potential for human ES cells is staggering. The foundation now exists for creating universal "stem cell banks" -- cells that can be pulled from a freezer, treated with the right mix of growth factors, and directed to form a specific tissue. Such cells could even be genetically manipulated to avoid attack by the patient's immune system. Researchers have already used embryonic stem cells to grow heart muscle cells that beat in unison in a culture dish, as well as critical craniofacial tissues like blood vessel cells, bone, cartilage, neurons, and skeletal muscle. Although many ethical issues remain to be resolved concerning the use of human ES cells, the future of biomimetics and tissue engineering looks very bright indeed.

A 1982 article in Therapeaia, entitled "Spare Body Parts", summed up the state of the science at that time by proposing "...the only limits in artificial organ research are the limits of the imagination." Perhaps the same philosophy can now be applied to bioengineered tissues, organs, and "body parts".



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