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Astonishing Advances in Tissue Regeneration

March 2006

By Heather S. Oliff, PhD

A Genetic Approach to Regeneration

Researchers at the Wistar Institute in Philadelphia, PA, are studying a unique strain of mouse that can heal wounds by regeneration. After a hole is pierced in the mouse’s ear (a typical laboratory identification procedure), it closes with no evidence that a hole was ever present.16 These animals, known as Murphy/Roths/Large mice, or MRL mice, are so named to denote the two scientists who originally bred them, as well as their unusually large size. MRL mice are genetically unique, and scientists are researching them to elucidate the genetics of regeneration, hoping to gather information that can be used to help humans.17

When the Wistar scientists induced heart injury in both MRL mice and typical mice, they found that the MRL mouse heart returned to normal, whereas the typical mouse heart was scarred.18 Human hearts scar following injury from heart attack, and the scarring response contributes to chronic heart disease and death.19 The healing response in the MRL mouse, however, differed greatly from that of the typical mouse. The MRL mouse displayed early movement of cardiomyocytes into the wound site, and DNA synthesis and proliferation of these cells.18 The MRL mouse heart also demonstrated better revascularization (restoration of blood supply) at the site of injury, which is necessary to help cells thrive and avoid death. According to the scientists, the MRL mouse studies demonstrate that “mammalian hearts have significant capacity to regenerate.”18

The Wistar scientists are now working to identify which genetic and biochemical factors are involved in this regenerative response. They have already identified areas on several chromosomes that control wound closure and are involved in regeneration of the MRL mouse ear tissue.19,20 It is unclear whether these same chromosomes are responsible for regenerating the MRL heart.18

A potential key mediator of regeneration is the family of enzymes known as the matrix metalloproteinases. These protein-digesting enzymes degrade the collagen that helps form scar tissue. They occur in immune cells, along with another family of molecules called the tissue inhibitors of metalloproteinase, which inhibit matrix metalloproteinases. After an injury, neutrophils that contain matrix metalloproteinases and tissue inhibitors of metalloproteinase enter the wound. Regeneration or scarring occurs depending on whether matrix metalloproteinases or tissue inhibitors of metalloproteinase dominate. The MRL mouse ear wound has a more active form of matrix metalloproteinases and lower levels of tissue inhibitors of metalloproteinase than the typical mouse ear wound.19 This combination promotes a regeneration process rather than a scarring process in the MRL mouse.19

The scientists also looked at the ability of MRL mice to heal central nervous system injuries.22 In the MRL mice, the matrix metalloproteinase response was temporarily increased following a brain injury, but the brain was not repaired differently than that of the typical mouse.22 The researchers hypothesize that the central nervous system has mechanisms to decrease the matrix metalloproteinase response, and that the tendency to scar blocks regenerative healing.17,19,22 Discovering how to prevent the formation of scar tissue may eventually make it possible to regenerate the heart, heal chronic wounds and burns, repair spinal tissue, and promote organ replacement.


The National Institutes of Health (NIH) has awarded $16.1 million over four years to fund a National Stem Cell Bank, NIH director Elias A. Zerhouni, MD, recently announced.

The National Stem Cell Bank, awarded to the WiCell Research Institute in Madison, WI, will be the nation’s first and only stem cell bank. As such, WiCell will be the keeper of all federally approved human embryonic stem cell lines, conducting molecular characterizations on each cell line, defining their growth properties, performing quality control, and distributing the cell lines to qualified research scientists worldwide.23

The WiCell Research Institute is a nonprofit organization founded in 1999 by James Thompson, PhD, a reproductive biologist who was the first to isolate human embryonic stem cell lines. Human embryonic stem cells are derived from embryos approximately six days after their fertilization in the laboratory, as part of an assisted reproductive program for infertile couples. Embryos potentially serving as a source of human embryonic stem cell lines are in excess of those required by the couples from which they were derived and are therefore destined to be discarded. There are currently more than 400,000 such surplus embryos in the US.

Because human embryonic stem cell lines are capable of self-renewal and propagating daughter cells with the potential to give rise to all tissue types, they have enormous potential in treating many currently untreatable diseases and medical conditions, such as type I diabetes mellitus, Parkinson’s disease, and spinal cord injuries. Current guidelines, established jointly by the National Research Council and the Institute of Medicine, provide for human embryonic stem cell line research in treating disease, while prohibiting human cloning.23

In addition to the WiCell grant, the NIH appointed the University of California, Davis, and Northwestern University as Centers of Excellence in Translational Human Stem Cell Research. The two Centers of Excellence will bring together stem cell experts, disease specialists, and other scientists to explore the use of human stem cells in treating a wide range of disease conditions.23

Tissue Engineering Holds Promise

Millions of dollars are spent each year to develop tissue engineering products and procedures. In fact, some engineered tissues have already been approved by the FDA.One of the first tissues to be engineered and used clinically is bone. Engineered bones, cartilage, tendons, and ligaments may benefit people who suffer from bones that will not fuse, defective tendons, or arthritic joints, as well as those who need dental implants (which require strong bone tissue). These regenerated tissues will one day eliminate the need for standard therapy, which includes stainless steel, cobalt chrome, and bone grafting.

Scientists are also developing engineered skin, which will help treat massive burns, chronic problem wounds that are difficult to heal (common in people with diabetes), and vitiligo (a disease of discolored skin). Although heart valves have been engineered, the valves failed when they were implanted.24 A whole bladder has been engineered and transplanted in a dog.25 The bladder appeared to be normal and demonstrated normal function.25 An engineered bladder has not been evaluated in humans. Nearly every body tissue is being engineered for future applications in medicine.

Three components are needed for successful tissue engineering: cells (such as stem cells), scaffold or matrix (which provides a degradable physical base for cell growth), and growth factors.26 Simply put, the cells grow along a physical scaffold, and specific growth factors stimulate cell activity and differentiation into the desired tissue.26

Three main techniques are now being studied : 1) injecting cells into the damaged tissue, either with or without a degradable scaffold; 2) growing a complete three-dimensional tissue to maturity in the laboratory and then implanting it into the patient; and 3) implanting a scaffold directly into the injured tissue, stimulating the body’s own cells to regenerate the tissue.27

Many challenges to achieving successful tissue engineering remain, however. For example, once it is placed into the body, the engineered tissue must be supplied with blood. New blood vessels must form quickly or the tissue will die. This presents a greater challenge in larger engineered tissues. The timing and appropriate doses of growth factors are still under investigation. Scientists are also developing optimal scaffolds that can guide the growth of cells within the patient.27


Remarkable advances in tissue regeneration and engineering hold great promise for curing diseases and prolonging life. One day, scientists and physicians may use stem cell therapies to regenerate damaged tissues and organs or to cure conditions such as Parkinson’s disease, arthritis, and diabetes. They may also be used to reverse the aging process.

As research into these extraordinary technologies continues to accelerate, the day when these possibilities become realities draws ever closer.


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