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The Scientist

by Charles Vacanti

VISION
Cells for Building
In tissue engineering, embryonic stem cells might not be the way to go


The Scientist 2004, 18(22):22

Published   22 November 2004


FRA ANGELICA'S "HEALING OF JUSTINIAN"

Tissue engineering has taken on a new meaning in recent years, bringing the stuff of science fiction to the operating table. Bone, cartilage, skin, and other organ tissues can now be grown from stem cells and implanted. Pushing beyond the mechanics of prosthetics, the advances in stem-cell biology and materials science have enabled startling accomplishments, including the replacement of a human breastbone, a thumb, and a rat spinal cord.

But, connections to the embryonic stem-cell ethical minefield bring a renewed need to evaluate our best options in moving forward. As the name implies, pluripotent embryonic stem cells are rife with potential but also with confounding factors even outside philosophical quagmires. I believe that further work with adult stem cells, which may skirt both ethical and technical difficulties, will lead us toward more success with tissue engineering.



A painting by Fra Angelica, "Healing of Justinian" (see above) depicting the transplantation of a limb by Saints Damian and Cosmas, is often referred to as the first historical reference to tissue engineering. The term had previously been associated with the use of prosthetic implants and surgical manipulation of tissues, but the science of tissue engineering, as it exists today, arose in Boston in the mid-1980s, first with the development of artificial skin by Ioannis Yannas and John Burke,[1] and then with engineered cartilage, described by us in 1991.[2]

The BBC brought tissue engineering's potential to the forefront of public awareness when it broadcast images of the infamous mouse with the human ear. The premise that new, functional, replacement tissue could be grown, using living cells seeded onto appropriately configured scaffolds, became very real. For artificial skin, cells can be seeded onto a naturally occurring scaffold composed of collagen fibers. For cartilage, the cells are seeded onto synthetic polymers and molded into the desired shape. The cell-polymer complex is then implanted under the recipient's skin, allowing the cells to be nourished, remain alive, and make new cartilage tissue. Over time, the scaf-folding degrades leaving only new, living cartilage.

In 1991 a young male patient, born without a breastbone, received a tissue-engineered cartilage implant, seeded with his own cells. The work was unpublished. In 1998, a similar operation was done to replace the distal thumb bone of a factory worker.[3] The patient received an implant composed of very porous coral seeded with his own bone cells.

An even more recent study demonstrates that cells taken from the spinal cords of rats could be placed on similar polymer scaf-foldings and used to regrow replacement spinal cord, which helped reverse paralysis in these injured rats.[4] These examples suggest a tremendous potential in generating new replacement parts for humans.

Although the promise is tremendous, it has only seldom been accomplished in humans, largely because many cells are needed to generate small amounts of tissue. To be effective, it will be necessary to generate large amounts of tissue, starting with very few cells. But mature cells, when allowed to multiply in an incubator, ultimately lose their effectiveness. Consequently, scientists are turning to other cell types.



To be effective, cells must be easily procured and readily available; they must multiply well without losing their potential to generate new functional tissue; they should not be rejected by the recipient and not turn into cancer; and they must have the ability to survive in the low-oxygen environment normally associated with surgical implantation.

Mature adult cells fail to meet many of these criteria. The oxygen demand of cells increases with their metabolic activity. After being expanded in the incubator for significant periods of time, they have a relatively high oxygen requirement and do not perform normally. A hepatocyte, for example, requires about 50 times more oxygen than a cell such as a chondrocyte. So, much attention has turned to progenitor cells and stem cells.

True stem cells can turn into any type of cell, while progenitor cells are more or less committed to becoming cell types of a particular tissue or organ. Adult stem cells may actually represent progenitor cells in that they may turn into all the cells of a specific tissue but not into any cell type. Adult stem cells can be procured from the individual needing the new tissue and thus not be rejected. Since these cells are immature, they will survive a low-oxygen environment.


Charles Vacanti

Although embryonic stem cells have been shown to have the potential to turn into virtually any cell type found within the body, no studies have demonstrated the controlled generation of a uniform cell type. And unless they are derived from somatic-cell nuclear transfer, embryonic stem cells will be rejected by a recipient.

In 2001 we discovered an adult stem cell, which we refer to as a "spore-like" cell, in virtually every tissue of the body.[5] These small cells, measuring 3 to 7 μm, have the ability to withstand hostile environments such as low oxygen, elevated temperature, and freeze-thaw cycles. I believe that the numerous adult stem cells and progenitor cells being described are all offspring of the same spore-like stem cell. In our studies we have learned that, as these cells develop and mature, they have the ability to turn into virtually any cell type seen in the body.

Based on experiments in our laboratory, I believe that spore-like adult stem cells are the body's natural repair cells activated by injury. When activated, they multiply and are programmed to mature and repair damaged tissue. Incidentally, if the damage is sufficient, these cells may lose their local environmental cues and remain in their high-multiplication phase without maturing. In this state they may have the potential to turn into cancer. These tiny, spore-like cells are small enough to be transported via the lymphatic system, enabling metastasis. Although I have no evidence to verify this hypothesis, it is an internally consistent model that may explain both the natural process of repair, and repair gone awry.

Regardless, such stem cells may ultimately allow physicians and scientists to repair or replace any tissue in the human body. The potential to reverse the symptoms of stroke and other central nervous system diseases such as Parkinson and Alzheimer is quite realistic. It may be possible to remove cells from diseased organs, genetically manipulate them, and return them to patients to cure their disease.




SEEDS FOR NEW CURES:Transmission electron micrograph of extremely small "spore-like" adult stem cells found in virtually every tissue of the body. They could be repair cells capable of turning into the mature cells of the organ or tissue from which they were initially isolated.

Both embryonic and adult stem cells appear to have similar potential to develop into the different cellular elements necessary for effective tissue replacement. The differences are few, but they may be significant. Some scientists believe that embryonic stem cells may have a greater ability to produce healthier tissue. This may or may not be the case.

My view may be biased, but after a careful review of the literature, I have concluded that the disadvantages of embryonic stem cells appear to outweigh the advantages. Embryonic stem cells will be recognized as foreign and be rejected. There is no evidence that embryonic stem cells can be consistently driven to uniformly generate only the cell type that is needed. While they can certainly be encouraged to form any type of cell, many other types of cells are usually generated at the same time. New nerve cells may be contaminated with bone or muscle, for example.

Perhaps most significant are the moral and ethical considerations surrounding the use of embryonic stem cells. Whether the embryo is a human being, or a meaningless aggregation of cells, remains unknown. If it is a worthless aggregate of living cells, then we may do well to undertake scientific investigations. If, on the other hand, the human embryo indeed represents a human being, then I believe it would be immoral to conduct scientific investigations.

If, at some point in time, an embryonic stem cell is determined to represent human life, we will be poorly judged as a society. When considering the seriousness of the issue, it seems reasonable to first demonstrate whether there is any real advantage to using embryonic cells, by studying nonhuman species, as this is a prerequisite in any other investigative field.

Charles Vacanti is the Vandam/Covino Professor of Anesthesia in the Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School, and anesthesiologist-in-chief at Brigham and Women's Hospital. He is one of four brothers involved in tissue engineering research and has repeatedly shaken the field with daring experiments and ideas for creating new implantable tissue.

He can be contacted at cvacanti@partners.org




1.   Yannas I, Burke J: "Successful use of a physiologically acceptable artificial skin in the treatment of extensive burn injury,".
Ann Surg 1981, 194:413-28.
    Return to citation in text: [1]
 
2.   Vacanti CA, et al.: "Synthetic polymers seeded with chondrocytes provides a template for new cartilage formation,".
Plast Reconstr Surg 1991, 88:753-9.
    Return to citation in text: [1]
 
3.   Vacanti CA, et al.: "Brief report: Replacement of an avulsed phalanx with tissue-engineered bone,".
N Engl J Med 2001, 344:1511-4. [Publisher Full Text]
    Return to citation in text: [1]
 
4.   Vacanti MP, et al.: "Tissue engineered spinal cord,".
Transplant Proc 2001, 33:592-8. [Publisher Full Text]
    Return to citation in text: [1]
 
5.   Vacanti MP, et al.: "Identification and initial characterization of spore-like cells in adult mammals,".
J Cell Biochem 2001, 80:455-60. [Publisher Full Text]

 

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