regeneration

(physiology)

The process by which an animal restores a lost part of its body. Broadly defined, the term can include wound healing, tissue repair, and many kinds of restorative activities. Within the field of developmental biology, however, most research in regeneration involves systems in which removing a complex structure or major part of an organism initiates a chain of events that produces a structure that duplicates the missing part both functionally and anatomically.

The best-known and most widely studied examples of regeneration are those involving epimorphosis, in which the lost structure is reproduced directly by a combination of cell proliferation and redifferentiation of new tissue. Examples can be found throughout the animal kingdom. Research on regenerating systems yields information regarding basic mechanisms of animal development. Noteworthy has been the progress in understanding the factors that control pattern formation in the development of complex structures, such as vertebrate limbs.

Mammals, birds, and reptiles have a much more poorly developed ability than amphibians and fish to regenerate complete organs, but nevertheless can reform missing tissue and restore function after partial removal of certain organs. For example, if part of the liver is cut away, the remaining portions increase in size to compensate for the missing tissue and to restore the normal functional capacity of the organ. The process of liver regeneration involves the triggering of active growth in the remaining liver cells, in cells of bile ductules, and in unspecialized cells called stem cells, all of which are usually quiescent in the normal liver. Proliferation of these cells and their subsequent differentiation are key events in the process by which the missing liver mass is replaced and adequate hepatic function restored. In the musculoskeletal system, different populations of quiescent stem cells allow efficient replacement of damaged or partially removed bones and muscles. See also Bone; Liver; Muscle.

Of all vertebrates, amphibians have the most highly developed capacity for regeneration. Certain species have the ability to regenerate not only limbs and tails but also parts of the eye, lower jaw, intestine, and heart. Complete regeneration of amputated limbs can occur throughout the lifetime of most salamanders and newts. In frogs and toads, the ability to regenerate limbs is lost during metamorphosis to the adult form.

Protozoa and simple multicellular animals, including sponges, coelenterates, and flatworms, display remarkable capacities for regeneration following various experimental manipulations. Regenerative ability in such organisms correlates closely with their capacity to reproduce asexually, most commonly by fission or by budding, and the mechanisms of growth involved in regeneration are often very similar to those of asexual propagation. For example, just as complete ciliated protozoa will develop after fission, which divides the nucleus and organelles between daughter cells, intact individuals will also be reconstituted from fragments of a single organism if the fragment contains a complete set of the genetic material and a portion of the original cell's cortical cytoplasm. Similar rules regarding the importance of the nucleus apply to regenerative processes in all protozoa.

Most annelids, such as the earthworm, can readily regenerate segments after their removal: some species can regenerate whole organisms from any fragment. Like more primitive invertebrates, certain annelids can reproduce asexually by transverse fission. The capacities for fission and for reconstitution from fragments in annelids are remarkable, considering the anatomical complexity of animals in this phylum. When an earthworm is cut transversely into two parts, the anterior part can regenerate several posterior segments. The ability of the posterior half to regenerate anterior segments is, however, more limited and is absent altogether in some species. Experiments in which components of the nervous system are removed surgically have revealed the importance of a neural influence for segment regeneration, presumably mediated by a growth-stimulating hormone secreted from neural cells. See also Annelida.

The ability of certain echinoderms, such as starfish, to regenerate missing arms is well known. Cutting such an animal into several pieces results in each piece forming a new organism, a phenomenon that usually requires the presence of at least some of the central portion of the body. Equally remarkable is a regenerative response shown by another echinoderm, the sea cucumber. When this animal is strongly irritated, it eviscerates itself through its anus or through a rupture of its body wall. This phenomenon produces a nearly empty sack of skin and muscle, which then proceeds to regenerate all the internal organs, beginning with the digestive tract. See also Echinodermata.

The capacity for appendage regeneration is widespread among the many diverse members of the phylum Arthropoda. In these complex animals with well-developed exoskeletons and no asexual mode of reproduction, regeneration shows a close correlation with the molting process. See also Arthropoda; Developmental biology.

Regeneration (engineering)

The process of feeding back a portion of the output signal of an amplifier to its input in such a way that the input signal is reinforced. The result is greatly increased amplification. The feedback must be positive; that is, the two signals must be in phase, and it must be limited in magnitude to prevent the circuit from going into oscillation. See also Feedback circuit.

In biology, regeneration is an organism's ability to replace body parts. Aside from being used to generally describe any number of specific healing processes, regeneration also is a specific method of healing that is noted for its ability to regrow lost limbs, severed nerve connections, and other wounds. It can be seen in the organisms of planaria and starfish.

Explanation

Regeneration occurs in many, if not all vertebrate types , and is present in some adult animals such as salamanders ( e.g. [1]). Mammals exhibit limited regenerative abilities, although not as impressive as salamanders. Examples of mammalian regeneration include antlers, finger tips and holes in ears. Finger tip regeneration has been well characterized, and these studies have resulted in the first demonstration of a genetic pathway controlling regeneration in a mammal. Several species of mammals can regenerate ear holes; a phenomenon that has been most studied in the MRL mouse. If the processes behind regeneration are fully understood, it is believed this would lead to better treatment for individuals with nerve injuries (such as those resulting from a broken back or a polio infection), missing limbs, and/or damaged or destroyed organs.

Regeneration of a lost limb occurs in two major steps, first de-differentiation of adult cells into a stem cell state similar to embryonic cells and second, development of these cells into new tissue more or less the same way it developed the first time [7]. Some animals like planarians instead keep clusters of non-differentiated cells within their bodies, which migrate to the parts of the body that need healing.

Regeneration in salamanders

In urodele amphibians (salamanders), the regeneration process begins immediately after amputation. Limb regeneration in the axolotl and newt have been extensively studied. After amputation, the epidermis migrates to cover the stump in less than 12 hours, forming a structure called the apical epidermal cap (AEC). Over the next several days there are changes in the underlying stump tissues that result in the formation of a blastema (a mass of dedifferentiated proliferating cells). As the blastema forms, pattern formation genes – such as HoxA and HoxD – are activated as they were when the limb was formed in the embryo [8,10]. The Distal tip of the limb (the autopod, which is the hand or foot) is formed first in the blastema. The intermediate portions of the pattern are filled in during growth of the blastema by the process of intercalation [7,8]. Motor neurons, muscle, and blood vessels grow with the regenerated limb, and reestablish the connections that were present prior to amputation. The time that this entire process takes varies according to the age of the animal, ranging from about a month to around three months in the adult and then the limb becomes fully functional.

In spite of the historically small size of the number of researchers studying limb regeneration, remarkable progress has been made recently in establishing Ambystoma (the axolotl) as a model genetic organism. This progress has been facilitated by advances in genomics, bioinformatics, and somatic cell transgenesis in other fields, that have created the opportunity to investigate the mechanisms of important biological properties, such as limb regeneration, in the axolotl [12]. The Ambystoma Genetic Stock Center (AGSC) is a self-sustaining, breeding colony of the Mexican axolotl (Ambystoma mexicanum) supported by the National Science Foundation as a Living Stock Collection. Located at the University of Kentucky, the AGSC is dedicated to supplying genetically well-characterized axolotl embryos, larvae, and adults to laboratories throughout the United States and abroad. An NIH-funded NCRR grant has led to the establishment of the Ambystoma EST database, the Salamander Genome Project (SGP) that has led to the creation of the first amphibian gene map and several annotated molecular data bases, and the creation of the research community web portal (www.ambystoma.org).

Regeneration of human fingers

Studies in the 1970s showed that children up to the age of 10 or so who lose fingertips in accidents can regrow the tip of the digit within a month provided their wounds are not sealed up with flaps of skin -- the de facto treatment in such emergencies.[14]

Regeneration of human ribs

Human ribs can regenerate if the periosteum, the membrane surrounding the rib, is left intact (Nadia Rosenthal in Howard Hughes Medical Institute "The 2006 Holiday Lectures on Science"). For this reason, ribs are used as a source of bone in reconstructive surgery. [13]

Regeneration of human liver

The human liver is one of the few glands in the body that has the ability to regenerate from as little as 25% of its tissue. This is largely due to the unipotency of hepatocytes.

Regeneration in MRL mice

Adult mammals have a limited regenerative response as compared to most vertebrate embryos/larvae and adult salamanders and fish. Among adult mammals, the MRL mouse is a strain of mice that exhibits enhanced regenerative abilities, and for this reason it has been a well studied model system for mammalian regeneration. Since adult salamanders exhibit such a remarkable regenerative ability, and species of mammals, such as the MRL mouse, also have regenerative abilities, it is thought that it should be possible to enhance the innate regenerative ability of humans.

By comparing the differential gene expression of scarless healing MRL mice and poor healing C57BL/6 mice strain, 36 genes have been identified that are good candidates for studying how the healing process differs in MRL mice and other mice.[1]

The regenerative abilities of MRL mice does however not protect against myocardial infarction. MRL mice show the same amount of cardiac injury and scar formation as normal mice after a heart attack.[2]

In fiction

Main article: Healing factor

In some fictional stories, the possibility for enhanced human regeneration is explored. Comic books, especially, have featured characters with such abilities. In these stories, human healing from injury is treated as a superpower. Usually, this "healing factor", as it is called, allows for rapid regeneration from injury in a very short period of time; usually a few seconds. Even normally fatal injuries are often overcome with relative ease. While the specifics sometimes differ, the factors are often presented as an inherent ability gained through human mutation/evolution, deliberate engineering or magic.

In the Comics and films of Xmen, Wolverine has the ability of accelerated healing

In the Television Series Doctor Who, Time Lords can 'regenerate'. They become totally new people, by replacing every cell in their body, but retaining the brain, effectively making them immortal.

In the Television Series Heroes, Claire Bennet the cheerleader can 'regenerate' spontaneously.

In the Anime series DragonBall Z, the character Piccolo can regenerate any part of his body immediately.

See also

• The Body Electric

External links

• Spallanzani's mouse: a model of restoration and regeneration
• Mice that regrow hearts in the news
• DARPA Grant Supports Research Toward Realizing Tissue Regeneration
• The Geniuses Of Regeneration in BusinessWeek, May 24, 2004
• UCI Limb Regeneration Lab

References

1. Biochem Biophys Res Commun. 2005 Apr 29;330(1):117-22. PMID 15781240
2. Wound Repair Regen. 2005 Mar-Apr;13(2):205-8. PMID 15828946
3. Tanaka EM. Cell differentiation and cell fate during urodele tail and limb regeneration. Curr Opin Genet Dev. 2003 Oct;13(5):497-501. PMID 14550415
4. Nye HL, Cameron JA, Chernoff EA, Stocum DL. Regeneration of the urodele limb: a review. Dev Dyn. 2003 Feb;226(2):280-94. PMID 12557206
5. Yu H, Mohan S, Masinde GL, Baylink DJ. Mapping the dominant wound healing and soft tissue regeneration QTL in MRL x CAST. Mamm Genome. 2005 Dec;16(12):918-24. PMID 16341671
6. Odelberg SJ.Unraveling the molecular basis for regenerative cellular plasticity.PLoS Biol. 2004 Aug;2(8):E232. PMID 15314652

1. Bryant, S.V., Endo, T. and Gardiner, D.M. Vertebrate limb regeneration and the origin of limb stem cells. Int. J. Dev. Biol. 2002 46:887-896. PMID 12455626
2. Gardiner DM, Blumberg B, Komine Y, Bryant SV. Regulation of HoxA expression in developing and regenerating axolotl limbs. Development. 1995 Jun;121(6):1731-41. PMID 7600989
3. Mullen LM, Bryant SV, Torok MA, Blumberg B, Gardiner DM. Nerve dependency of regeneration: the role of Distal-less and FGF signaling in amphibian limb regeneration. Development. 1996 Nov;122(11):3487-97. PMID 8951064
4. Torok MA, Gardiner DM, Shubin NH, Bryant SV. Expression of HoxD genes in developing and regenerating axolotl limbs. Dev Biol. 1998 Aug 15;200(2):225-33. PMID 9705229
5. Endo T, Bryant SV, Gardiner DM. A stepwise model system for limb regeneration. Dev Biol. 2004 Jun 1;270(1):135-45. PMID 15136146
6. Putta S, Smith JJ, Walker JA, Rondet M, Weisrock DW, Monaghan J, Samuels AK, Kump K, King DC, Maness NJ, Habermann B, Tanaka E, Bryant SV, Gardiner DM, Parichy DM, Voss SR, From biomedicine to natural history research: EST resources for ambystomatid salamanders. BMC Genomics. 2004 Aug 13;5(1):54. PMID 15310388
7. Wieland, C, Regenerating ribs. Creation. 1989 September;21(4):46-47. [2]
8. Weintraub, Arlene , The Geniuses Of Regeneration. 2004 MAY [3]

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