Astonishing Advances in Tissue RegenerationMarch 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.
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.
1. Available at: http://stemcells.nih.gov/info/ scireport. Accessed December 7, 2005.
2. Chung Y, Klimanskaya I, Becker S, et al. Embryonic and extraembryonic stem cell lines derived from single mouse blastomeres. Nature. 2005 Oct 16.
3. Shake JG, Gruber PJ, Baumgartner WA, et al. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg. 2002 Jun;73(6):1919-25.
4. Barbash IM, Chouraqui P, Baron J, et al. Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation. 2003 Aug 19;108(7):863-8.
5. Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA. 2001 Aug 28;98(18):10344-9.
6. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001 Apr 5;410(6829):701-5.
7. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002 Jan 1;105(1):93-8.
8. Available at: http://www.miami.com/mld/ miamiherald/living/people/13378563.htm. Accessed December 15, 2005.
9. Assmus B, Schachinger V, Teupe C, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002 Dec 10;106(24):3009-17.
10. Strauer BE, Brehm M, Zeus T, et al. Intracoronary, human autologous stem cell transplantation for myocardial regeneration following myocardial infarction. Dtsch Med Wochenschr. 2001 Aug 24;126(34-35):932-8.
11. Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002 Oct 8;106(15):1913-8.
12. Tse HF, Kwong YL, Chan JK, et al. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet. 2003 Jan 4;361(9351):47-9.
13. Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomized controlled clinical trial. Lancet. 2004 Jul 10;364(9429):141-8.
14. Keirstead HS, Nistor G, Bernal G, et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005 May 11;25(19):4694-705.
15. Available at: http://www.nytimes.com/ 2005/12/13/science/13brain.html. Accessed December 13, 2005.
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.
23. Available at: www.nih.gov/news/pr/ oct2005/od-03.htm. Accessed October 6, 2005.
24. Vesely I. Heart valve tissue engineering. Circ Res. 2005 Oct 14;97(8):743-55.
25. Oberpenning F, Meng J, Yoo JJ, Atala A. De novo reconstitution of a functional mammalian urinary bladder by tissue engineering. Nat Biotechnol. 1999 Feb;17(2):149-55.
26. Available at: http://www.medscape.com/ viewarticle/413101. Accessed December 7, 2005.
27. Griffith LG, Naughton G. Tissue engineering—current challenges and expanding opportunities. Science. 2002 Feb 8;295(5557):1009-14