Astonishing Advances in Tissue Regeneration

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.

References
16. Clark LD, Clark RK, Heber-Katz E. A new murine model for mammalian wound repair and regeneration. Clin Immunol Immunopathol. 1998 Jul;88(1):35-45.
17. Bedelbaeva K, Gourevitch D, Clark L, et al. The MRL mouse heart healing response shows donor dominance in allogeneic fetal liver chimeric mice. Cloning Stem Cells. 2004;6(4):352-63.
18. Leferovich JM, Bedelbaeva K, Samulewicz S, et al. Heart regeneration in adult MRL mice. Proc Natl Acad Sci USA. 2001 Aug 14;98(17):9830-5.
19. Heber-Katz E, Leferovich J, Bedelbaeva K, Gourevitch D, Clark L. The scarless heart and the MRL mouse. Philos Trans R Soc Lond B Biol Sci. 2004 May 29;359(1445):785-93.
20. McBrearty BA, Clark LD, Zhang XM, Blankenhorn EP, Heber-Katz E. Genetic analysis of a mammalian wound-healing trait. Proc Natl Acad Sci USA. 1998 Sep 29;95(20):11792-7.
21. Heber-Katz E, Chen P, Clark L, et al. Regeneration in MRL mice: further genetic loci controlling the ear hole closure trait using MRL and M.m. Castaneus mice. Wound Repair Regen. 2004 May;12(3):384-92.
22. Hampton DW, Seitz A, Chen P, Heber-Katz E, Fawcett JW. Altered CNS response to injury in the MRL/MpJ mouse. Neuroscience. 2004;127(4):821-32.