Researchers Seek Common Ground On Regeneration

Ah, the privileged life of a salamander. Chop off a limb, and within days a new one grows in its place. In recent years, scientists have become increasingly interested in tracing the molecular origins of this seemingly magical ability. By harnessing the mechanisms involved in a number of animal models, researchers hope to one day grow a variety of new human tissues in place of the old or defective, thereby supplanting the need for less "natural" remedies such as bionic limbs or organ transplantation. Unlike common wound healing, regeneration leaves a perfect replacement of the original tissue without scarring. Driven by basic research advances in cell and developmental biology, immunology, and surface and polymer chemistry, regenerative biology generally involves either the transplantation of isolated adult, fetal, or stem cells, the implantation of bioartificial tissues into a biodegradable scaffold or matrix, or the induction of regeneration in situ. Despite progress in applying regeneration technologies to humans, problems persist: Bone regeneration has been hampered because of the poor weight-bearing capability and low resorbability of the ceramic scaffold materials used. Skin regeneration efforts have been effective, but the cosmetic outcome is often far less than perfect. Although long the domain of investigators working on amphibians, recent work on mammals has made basic research on regeneration more relevant to humans. Researchers studying tissue and cell regeneration in amphibians and mammals assembled, perhaps for the first time, at a symposium at the Wistar Institute in Philadelphia entitled "Regeneration in the 21st Century," in early May. "The amphibian regeneration people have been considered to be studying something that doesn't relate to mammals, and that's absolutely not true. [Their work is] very related and I think that both groups can learn a lot from each other," says conference organizer Ellen Heber-Katz, an immunologist at Wistar. Although vertebrate limb regeneration is generally a hallmark of amphibians--specifically an order called urodela that includes salamanders--stem cells in bone and skin do facilitate tissue regeneration in all vertebrates by replenishing those cells when needed. Attempts to coax mesenchymal stem cells (MSCs) from bone marrow into other desired cell types in vitro and in vivo--thus providing an unlimited supply of therapeutic regenerative cells--remain promising. Researchers from Osiris Therapeutics and the Johns Hopkins University School of Medicine recently succeeded in getting MSCs from adult bone marrow to differentiate into cartilage, fat, and bone cells in vitro. 1,2 And in a May 14 Science paper, University of Pittsburgh Medical Center scientists announced proof that bone marrow cells can give rise to functional rat liver cells, probably via an intermediate oval cell. 3 It's the first report that these stem cells can provide a lineage for epithelial cells, which have the potential to develop into organs. Ideally, such cells could eventually be used to repair or replace injured or diseased livers in humans. Such findings might lessen the need for harvesting stem cells from embryos; although embryonic stem cell research has been all the rage of late, bioethical concerns threaten to limit their use in the laboratory. 4 "I think what we're seeing is a shift from the era of gene engineering to the era of cell engineering," remarks Ronald McKay, chief of the laboratory of molecular biology at the National Institute of Neurological Disorders and Stroke and a speaker at the Wistar symposium. "It's going to be quite interesting to see whether you have to have groups of different cells or whether a given pure cell can generate all the types and then generate a complex outcome." McKay's presentation on his lab's neural stem cell research was one of several at the symposium focusing on neurogenesis, a very active area of research. 5 Stem cells hint at a more widespread latent regenerative ability in all animals. "Regeneration is probably a very simple, a very basic characteristic of all living organisms," Alejandro Sánchez Alvarado of the Carnegie Institute of Washington in Washington, D.C., said at the symposium. He noted that the more complex the organism, the higher the number of regulatory checkpoints involved in their ability to regenerate. "The question is why some organisms can regenerate and others can't." Urodele amphibians regenerate limbs by undergoing cell dedifferention at the site of the wound to form a mass of cells called a blastema; the blastema then differentiates into the needed cell types. Co-organizer of the symposium David Stocum of Indiana-Purdue University Indianapolis (IUPUI) pointed out two reasons why mammalian tissue might not regenerate: lack of stem or progenitor cells, or, even if those cells are present, a lack of the essential stimulatory environment necessary for regeneration. To understand why regeneration occurs, many investigators examine its molecular underpinnings. Sánchez Alvarado's research began in the tadpole. But, like most skilled vertebrate regenerators, the tadpole isn't a tractable model for genetics studies. His lab chose to expand research to include an invertebrate model, the planarian or flatworm. Applying the same methodological approach to the planarian, they've begun to isolate some of the animal's genes that seem to be responsible for regeneration. 6 Interestingly, several of them are matrix metalloproteinases (MMPs), enzymes implicated in cell migration in other animals. Susan V. Bryant, a developmental biologist at the University of California, Irvine, explained how her lab has been trying to get a profile of genes expressed during different times of regeneration in Mexican salamanders called axolotls. They've found that two members of the HoxD complex of genes, part of a group of Hox genes known to be crucial to development in several species, are induced as a result of wounding. 7 And they've shown that the axolotl homologue of the Msx-2 (or Hox-8) gene, one of a family of transcription factors known to be expressed during embryogenesis, is being expressed during limb regeneration in axolotls. 8 Jeremy P. Brockes of the University College London presented preliminary evidence of a factor, possibly a ligand downstream from the blood-clotting enzyme thrombin, that's critical to initiating regeneration by coaxing cells back into the cell cycle. 9 His conclusions are based on studies of the newt skeletal myotube, a differentiated cell type. "We think ... that there is some relatively ubiquitous signal [that] acts on the differentiated urodele cells and that for some reason the mammalian cells have completely lost responsiveness," explained Brockes. But could that responsiveness somehow be revived? Heber-Katz reviewed her recent work on a line of mutant mice, which, she believes, have demonstrated regeneration. 10 She accidentally discovered the candidate regenerator about five years ago while conducting an experiment on autoimmune diseases. Holes punched in the ears of some of the experimental animals unexpectedly closed in a matter of weeks. Subsequent studies suggested that the observed phenomenon was regeneration and not simply wound healing--there was complete cartilage replacement without scarring. According to Heber-Katz's lab and others, mammals' poor regenerative capacity may be the result of an evolutionary trade-off: While amphibians are good regenerators with relatively simple immune systems, mammals regenerate poorly but possess complex immune systems. The multistep T-cell response that has developed in mammals could be intended to defend against tumors that share antigens with regenerating tissue--the ability to regenerate is therefore suppressed. Heber-Katz's lab is currently trying to find the genetic origins of regeneration in their mouse model. 11 They believe that the genes responsible are located on chromosomes 7, 8, 12, 13, and/or 15; the genes Msx-2 on chromosome 13 and keratin 1 on chromosome 15 are among their most promising candidates. However, identification of certain genes or factors integral to regeneration is likely just the first step in a much more complicated investigation. "Genes are only some kind of tool, some kind of handle where we can start going in and really asking the questions as to why [regeneration] happens," said Sánchez Alvarado at the conclusion of his talk. "The key thing is to identify what the choreography of gene expression is going to be-how are these genes deployed in the tissue." M.F. Pittenger et al., "Multilineage potential of adult human mesenchymal stem cells," Science, 284 :143-7, April 2, 1999. R. Lewis, "Human mesenchymal stem cells differentiate in the lab," The Scientist, 3 [8]:1, April 12, 1999. B. Petersen et al., "Bone marrow as potential source of hepatic oval cells," Science, 284:1168-70, May 14, 1999. Notebook, "Stem cell shuffle," The Scientist, 13 [3]:31, Feb. 1, 1999. A.J.S. Rayl, "Neurogenesis: research turns another 'fact' into myth," The Scientist, 13 [4]:16, Feb. 15, 1999. A.S. Alvarado, P.A. Newmark, "The use of planarians to dissect the molecular basis of metazoan regeneration," Wound Repair and Regeneration, 6 :413-20, July-August 1998. M.A. Torok et al., "Expression of HoxD genes in developing and regenerating axolotl limbs," Developmental Biology, 200 :225-33, Aug. 15, 1998. M.R.J. Carlson et al., "Expression of Msx-2 during development, regeneration, and wound healing in axolotl limbs," Journal of Experimental Zoology, 282 :715-23, Dec. 15, 1998. E.M. Tanaka, J.P. Brockes, "A target of thrombin activation promotes cell cycle re-entry by urodele muscle cells," Wound Repair and Regeneration, 6 :371-81, July-August 1998. Notebook, "Mouse tales," The Scientist, 12 [6]:31, March 16, 1998. B.A. McBrearty et al., "Genetic analysis of a mammalian wound-healing trait," Proceedings of the National Academy of Sciences, 95 :11792-7, Sept. 29, 1998.

Researchers Seek Common Ground On Regeneration

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Eugene Russo

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May 1999

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