In biology, regeneration is the process of renewal, restoration, and growth that makes genomes, cells, organisms, and ecosystems resilient to natural fluctuations or events that cause disturbance or damage. Every species is capable of regeneration, from bacteria to humans. Regeneration can either be complete where the new tissue is the same as the lost tissue, or incomplete where after the necrotic tissue comes fibrosis. At its most elementary level, regeneration is mediated by the molecular processes of gene regulation. Regeneration in biology, however, mainly refers to the morphogenic processes that characterize the phenotypic plasticity of traits allowing multi-cellular organisms to repair and maintain the integrity of their physiological and morphological states. Above the genetic level, regeneration is fundamentally regulated by asexual cellular processes. Regeneration is different from reproduction. For example, hydra perform regeneration but reproduce by the method of budding.
The hydra and the planarian flatworm have long served as model organisms for their highly adaptive regenerative capabilities. Once wounded, their cells become activated and start to remodel tissues and organs back to the pre-existing state. The Caudata ("urodeles"; salamanders and newts), an order of tailed amphibians, is possibly the most adept vertebrate group at regeneration, given their capability of regenerating limbs, tails, jaws, eyes and a variety of internal structures. The regeneration of organs is a common and widespread adaptive capability among metazoan creatures. In a related context, some animals are able to reproduce asexually through fragmentation, budding, or fission. A planarian parent, for example, will constrict, split in the middle, and each half generates a new end to form two clones of the original.
Echinoderms (such as the sea star), crayfish, many reptiles, and amphibians exhibit remarkable examples of tissue regeneration. The case of autotomy, for example, serves as a defensive function as the animal detaches a limb or tail to avoid capture. After the limb or tail has been autotomized, cells move into action and the tissues will regenerate. Limited regeneration of limbs occurs in most fishes and salamanders, and tail regeneration takes place in larval frogs and toads (but not adults). The whole limb of a salamander or a triton will grow again and again after amputation. In reptiles, chelonians, crocodilians and snakes are unable to regenerate lost parts, but many (not all) kinds of lizards, geckos and iguanas possess regeneration capacity in a high degree. Usually, it involves dropping a section of their tail and regenerating it as part of a defense mechanism. While escaping a predator, if the predator catches the tail, it will disconnect.
Ecosystems can be regenerative. Following a disturbance, such as a fire or pest outbreak in a forest, pioneering species will occupy, compete for space, and establish themselves in the newly opened habitat. The new growth of seedlings and community assembly process is known as regeneration in ecology.
Cellular molecular fundamentalsEdit
Pattern formation in the morphogenesis of an animal is regulated by genetic induction factors that put cells to work after damage has occurred. Neural cells, for example, express growth-associated proteins, such as GAP-43, tubulin, actin, an array of novel neuropeptides, and cytokines that induce a cellular physiological response to regenerate from the damage. Many of the genes that are involved in the original development of tissues are reinitialized during the regenerative process. Cells in the primordia of zebrafish fins, for example, express four genes from the homeobox msx family during development and regeneration.
"Strategies include the rearrangement of pre-existing tissue, the use of adult somatic stem cells and the dedifferentiation and/or transdifferentiation of cells, and more than one mode can operate in different tissues of the same animal. All these strategies result in the re-establishment of appropriate tissue polarity, structure and form.":873 During the developmental process, genes are activated that serve to modify the properties of cell as they differentiate into different tissues. Development and regeneration involves the coordination and organization of populations cells into a blastema, which is "a mound of stem cells from which regeneration begins". Dedifferentiation of cells means that they lose their tissue-specific characteristics as tissues remodel during the regeneration process. This should not be confused with the transdifferentiation of cells which is when they lose their tissue-specific characteristics during the regeneration process, and then re-differentiate to a different kind of cell.
Arthropods are known to regenerate appendages following loss or autotomy. Regeneration among arthropods is restricted by molting such that hemimetabolous insects are capable of regeneration only until their final molt whereas most crustaceans can regenerate throughout their lifetimes. Molting cycles are hormonally regulated in arthropods, although premature molting can be induced by autotomy. Mechanisms underlying appendage regeneration in hemimetabolous insects and crustaceans is highly conserved. During limb regeneration species in both taxa form a blastema following autotomy with regeneration of the excised limb occurring during proecdysis. Arachnids, including scorpions, are known to regenerate their venom, although the content of the regenerated venom is different than the original venom during its regeneration, as the venom volume is replaced before the active proteins are all replenished.
Many annelids (segmented worms) are capable of regeneration. For example, Chaetopterus variopedatus and Branchiomma nigromaculata can regenerate both anterior and posterior body parts after latitudinal bisection. The relationship between somatic and germline stem cell regeneration has been studied at the molecular level in the annelid Capitella teleta. Leeches, however, appear incapable of segmental regeneration. Furthermore, their close relatives, the branchiobdellids, are also incapable of segmental regeneration. However, certain individuals, like the lumbriculids, can regenerate from only a few segments. Segmental regeneration in these animals is epimorphic and occurs through blastema formation. Segmental regeneration has been gained and lost during annelid evolution, as seen in oligochaetes, where head regeneration has been lost three separate times.
Along with epimorphosis, some polychaetes like Sabella pavonina experience morphallactic regeneration. Morphallaxis involves the de-differentiation, transformation, and re-differentation of cells to regenerate tissues. How prominent morphallactic regeneration is in oligochaetes is currently not well understood. Although relatively under-reported, it is possible that morphallaxis is a common mode of inter-segment regeneration in annelids. Following regeneration in L. variegatus, past posterior segments sometimes become anterior in the new body orientation, consistent with morphallaxis.
Following amputation, most annelids are capable of sealing their body via rapid muscular contraction. Constriction of body muscle can lead to infection prevention. In certain species, such as Limnodrilus, autolysis can be seen within hours after amputation in the ectoderm and mesoderm. Amputation is also thought to cause a large migration of cells to the injury site, and these form a wound plug.
Tissue regeneration is widespread among echinoderms and has been well documented in starfish (Asteroidea), sea cucumbers (Holothuroidea), and sea urchins (Echinoidea). Appendage regeneration in echinoderms has been studied since at least the 19th century. In addition to appendages, some species can regenerate internal organs and parts of their central nervous system. In response to injury starfish can autotomize damaged appendages. Autotomy is the self-amputation of a body part, usually an appendage. Depending on severity, starfish will then go through a four-week process where the appendage will be regenerated. Some species must retain mouth cells in order to regenerate an appendage, due to the need for energy. The first organs to regenerate, in all species documented to date, are associated with the digestive tract. Thus, most knowledge about visceral regeneration in holothurians concerns this system.
Regeneration research using Planarians began in the late 1800s and was popularized by T.H. Morgan at the beginning of the 20th century. Alejandro Sanchez-Alvarado and Philip Newmark transformed planarians into a model genetic organism in the beginning of the 20th century to study the molecular mechanisms underlying regeneration in these animals. Planarians exhibit an extraordinary ability to regenerate lost body parts. For example, a planarian split lengthwise or crosswise will regenerate into two separate individuals. In one experiment, T.H. Morgan found that a piece corresponding to 1/279th of a planarian or a fragment with as few as 10,000 cells can successfully regenerate into a new worm within one to two weeks. After amputation, stump cells form a blastema formed from neoblasts, pluripotent cells found throughout the planarian body. New tissue grows from neoblasts with neoblasts comprising between 20 and 30% of all planarian cells. Recent work has confirmed that neoblasts are totipotent since one single neoblast can regenerate an entire irradiated animal that has been rendered incapable of regeneration. In order to prevent starvation a planarian will use their own cells for energy, this phenomenon is known as de-growth.
Limb regeneration in the axolotl and newt has been extensively studied and researched. Urodele amphibians, such as salamanders and newts, display the highest regenerative ability among tetrapods. As such, they can fully regenerate their limbs, tail, jaws, and retina via epimorphic regeneration leading to functional replacement with new tissue. Salamander limb regeneration occurs in two main steps. First, the local cells dedifferentiate at the wound site into progenitor to form a blastema. Second, the blastemal cells will undergo proliferation, patterning, differentiation and growth using similar genetic mechanisms that deployed during embryonic development. Ultimately, blastemal cells will generate all the cells for the new structure.
After amputation, the epidermis migrates to cover the stump in 1–2 hours, forming a structure called the wound epithelium (WE). Epidermal cells continue to migrate over the WE, resulting in a thickened, specialized signaling center called the apical epithelial 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. The positional identity of the distal tip of the limb (i.e. the autopod, which is the hand or foot) is formed first in the blastema. Intermediate positional identities between the stump and the distal tip are then filled in through a process called intercalation. 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. Researchers at Australian Regenerative Medicine Institute at Monash University, have published that when macrophages, which eat up material debris, were removed, salamanders lost their ability to regenerate and formed scarred tissue instead.
In spite of the historically few researchers studying limb regeneration, remarkable progress has been made recently in establishing the neotenous amphibian the axolotl (Ambystoma mexicanum) 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. The Ambystoma Genetic Stock Center (AGSC) is a self-sustaining, breeding colony of the axolotl 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.
Anurans can only regenerate their limbs during embryonic development. Once the limb skeleton has developed regeneration does not occur (Xenopus can grow a cartilaginous spike after amputation). Reactive oxygen species (ROS) appear to be required for a regeneration response in the anuran larvae. ROS production is essential to activate the Wnt signaling pathway, which has been associated with regeneration in other systems. Limb regeneration in salamanders occurs in two major steps. First, adult cells de-differentiate into progenitor cells which will replace the tissues they are derived from. Second, these progenitor cells then proliferate and differentiate until they have completely replaced the missing structure.
Hydra is a genus of freshwater polyp in the phylum Cnidaria with highly proliferative stem cells that gives them the ability to regenerate their entire body. Any fragment larger than a few hundred epithelial cells that is isolated from the body has the ability to regenerate into a smaller version of itself. The high proportion of stem cells in the hydra supports its efficient regenerative ability.
Regeneration among hydra occurs as foot regeneration arising from the basal part of the body, and head regeneration, arising from the apical region. Regeneration tissues that are cut from the gastric region contain polarity, which allows them to distinguish between regenerating a head in the apical end and a foot in the basal end so that both regions are present in the newly regenerated organism. Head regeneration requires complex reconstruction of the area, while foot regeneration is much simpler, similar to tissue repair. In both foot and head regeneration, however, there are two distinct molecular cascades that occur once the tissue is wounded: early injury response and a subsequent, signal-driven pathway of the regenerating tissue that leads to cellular differentiation. This early-injury response includes epithelial cell stretching for wound closure, the migration of interstitial progenitors towards the wound, cell death, phagocytosis of cell debris, and reconstruction of the extracellular matrix.
Regeneration in hydra has been defined as morphallaxis, the process where regeneration results from remodeling of existing material without cellular proliferation. If a hydra is cut into two pieces, the remaining severed sections form two fully functional and independent hydra, approximately the same size as the two smaller severed sections. This occurs through the exchange and rearrangement of soft tissues without the formation of new material.
Owing to a limited literature on the subject, birds are believed to have very limited regenerative abilities as adults. Some studies on roosters have suggested that birds can adequately regenerate some parts of the limbs and depending on the conditions in which regeneration takes place, such as age of the animal, the inter-relationship of the injured tissue with other muscles, and the type of operation, can involve complete regeneration of some musculoskeletal structure. Werber and Goldschmidt (1909) found that the goose and duck were capable of regenerating their beaks after partial amputation and Sidorova (1962) observed liver regeneration via hypertrophy in roosters. Birds are also capable of regenerating the hair cells in their cochlea following noise damage or ototoxic drug damage. Despite this evidence, contemporary studies suggest reparative regeneration in avian species is limited to periods during embryonic development. An array of molecular biology techniques have been successful in manipulating cellular pathways known to contribute to spontaneous regeneration in chick embryos. For instance, removing a portion of the elbow joint in a chick embryo via window excision or slice excision and comparing joint tissue specific markers and cartilage markers showed that window excision allowed 10 out of 20 limbs to regenerate and expressed joint genes similarly to a developing embryo. In contrast, slice excision did not allow the joint to regenerate due to the fusion of the skeletal elements seen by an expression of cartilage markers.
Similar to the physiological regeneration of hair in mammals, birds can regenerate their feathers in order to repair damaged feathers or to attract mates with their plumage. Typically, seasonal changes that are associated with breeding seasons will prompt a hormonal signal for birds to begin regenerating feathers. This has been experimentally induced using thyroid hormones in the Rhode Island Red Fowls.
Mammals are capable of cellular and physiological regeneration, but have generally poor reparative regenerative ability across the group. Examples of physiological regeneration in mammals include epithelial renewal (e.g., skin and intestinal tract), red blood cell replacement, antler regeneration and hair cycling. Male deer lose their antlers annually during the months of January to April then through regeneration are able to regrow them as an example of physiological regeneration. A deer antler is the only appendage of a mammal that can be regrown every year. While reparative regeneration is a rare phenomenon in mammals, it does occur. A well-documented example is regeneration of the digit tip distal to the nail bed. Reparative regeneration has also been observed in rabbits, pikas and African spiny mice. In 2012, researchers discovered that two species of African Spiny Mice, Acomys kempi and Acomys percivali, were capable of completely regenerating the autotomically released or otherwise damaged tissue. These species can regrow hair follicles, skin, sweat glands, fur and cartilage. In addition to these two species, subsequent studies demonstrated that Acomys cahirinus could regenerate skin and excised tissue in the ear pinna.
Despite these examples, it is generally accepted that adult mammals have limited regenerative capacity compared to most vertebrate embryos/larvae, adult salamanders and fish. But the regeneration therapy approach of Robert O. Becker, using electrical stimulation, has shown promising results for rats and mammals in general.
Some researchers have also claimed that the MRL mouse strain exhibits enhanced regenerative abilities. Work comparing the differential gene expression of scarless healing MRL mice and a poorly-healing C57BL/6 mouse strain, identified 36 genes differentiating the healing process between MRL mice and other mice. Study of the regenerative process in these animals is aimed at discovering how to duplicate them in humans, such as deactivation of the p21 gene. However, recent work has shown that MRL mice actually close small ear holes with scar tissue, rather than regeneration as originally claimed.
MRL mice are not protected against myocardial infarction; heart regeneration in adult mammals (neocardiogenesis) is limited, because heart muscle cells are nearly all terminally differentiated. MRL mice show the same amount of cardiac injury and scar formation as normal mice after a heart attack. However, recent studies provide evidence that this may not always be the case, and that MRL mice can regenerate after heart damage. 
The regrowth of lost tissues or organs in the human body is being researched. Some tissues such as skin regrow quite readily; others have been thought to have little or no capacity for regeneration, but ongoing research suggests that there is some hope for a variety of tissues and organs. Human organs that have been regenerated include the bladder, vagina and the penis.
As are all metazoans, humans are capable of physiological regeneration (i.e. the replacement of cells during homeostatic maintenance that does not necessitate injury). For example, the regeneration of red blood cells via erythropoiesis occurs through the maturation of erythrocytes from hematopoietic stem cells in the bone marrow, their subsequent circulation for around 90 days in the blood stream, and their eventual cell-death in the spleen. Another example of physiological regeneration is the sloughing and rebuilding of a functional endometrium during each menstrual cycle in females in response to varying levels of circulating estrogen and progesterone.
However, humans are limited in their capacity for reparative regeneration, which occurs in response to injury. One of the most studied regenerative responses in humans is the hypertrophy of the liver following liver injury. For example, the original mass of the liver is re-established in direct proportion to the amount of liver removed following partial hepatectomy, which indicates that signals from the body regulate liver mass precisely, both positively and negatively, until the desired mass is reached. This response is considered cellular regeneration (a form of compensatory hypertrophy) where the function and mass of the liver is regenerated through the proliferation of existing mature hepatic cells (mainly hepatocytes), but the exact morphology of the liver is not regained. This process is driven by growth factor and cytokine regulated pathways. The normal sequence of inflammation and regeneration does not function accurately in cancer. Specifically, cytokine stimulation of cells leads to expression of genes that change cellular functions and suppress the immune response.
Adult neurogenesis is also a form of cellular regeneration. For example, hippocampal neuron renewal occurs in normal adult humans at an annual turnover rate of 1.75% of neurons. Cardiac myocyte renewal has been found to occur in normal adult humans, and at a higher rate in adults following acute heart injury such as infarction. Even in adult myocardium following infarction, proliferation is only found in around 1% of myocytes around the area of injury, which is not enough to restore function of cardiac muscle. However, this may be an important target for regenerative medicine as it implies that regeneration of cardiomyocytes, and consequently of myocardium, can be induced.
Another example of reparative regeneration in humans is fingertip regeneration, which occurs after phalange amputation distal to the nail bed (especially in children) and rib regeneration, which occurs following osteotomy for scoliosis treatment (though usually regeneration is only partial and may take up to 1 year).
The ability and degree of regeneration in reptiles differs among the various species, but the most notable and well-studied occurrence is tail-regeneration in lizards. In addition to lizards, regeneration has been observed in the tails and maxillary bone of crocodiles and adult neurogenesis has also been noted. Tail regeneration has never been observed in snakes. Lizards possess the highest regenerative capacity as a group. Following autotomous tail loss, epimorphic regeneration of a new tail proceeds through a blastema-mediated process that results in a functionally and morphologically similar structure.
Studies have shown that some chondrichthyans can regenerate rhodopsin by cellular regeneration, micro RNA organ regeneration, teeth physiological teeth regeneration, and reparative skin regeneration. Rhodopsin regeneration has been studied in skates and rays. After complete photo-bleaching, rhodopsin can completely regenerate within 2 hours in the retina. White bamboo sharks can regenerate at least two-thirds of their liver and this has been linked to three micro RNAs, xtr-miR-125b, fru-miR-204, and has-miR-142-3p_R-. In one study two thirds of the liver was removed and within 24 hours more than half of the liver had undergone hypertrophy. Leopard sharks routinely replace their teeth every 9–12 days  and this is an example of physiological regeneration. This can occur because shark teeth are not attached to a bone, but instead are developed within a bony cavity. It has been estimated that the average shark loses about 30,000 to 40,000 teeth in a lifetime. Some sharks can regenerate scales and even skin following damage. Within two weeks of skin wounding the mucus is secreted into the wound and this initiates the healing process. One study showed that the majority of the wounded area was regenerated within 4 months, but the regenerated area also showed a high degree of variability.
- Birbrair A, Zhang T, Wang ZM, Messi ML, Enikolopov GN, Mintz A, Delbono O (August 2013). "Role of pericytes in skeletal muscle regeneration and fat accumulation". Stem Cells and Development. 22 (16): 2298–314. doi:10.1089/scd.2012.0647. PMC 3730538. PMID 23517218.
- Carlson BM (2007). Principles of Regenerative Biology. Elsevier Inc. p. 400. ISBN 978-0-12-369439-3.
- Gabor MH, Hotchkiss RD (March 1979). "Parameters governing bacterial regeneration and genetic recombination after fusion of Bacillus subtilis protoplasts". Journal of Bacteriology. 137 (3): 1346–53. PMC 218319. PMID 108246.
- Min S, Wang SW, Orr W (2006). "Graphic general pathology: 2.2 complete regeneration". Pathology. pathol.med.stu.edu.cn. Archived from the original on 2012-12-07. Retrieved 2012-12-07.
(1) Complete regeneration: The new tissue is the same as the tissue that was lost. After the repair process has been completed, the structure and function of the injured tissue are completely normal
- Min S, Wang SW, Orr W (2006). "Graphic general pathology: 2.3 Incomplete regeneration:". Pathology. pathol.med.stu.edu.cn. Archived from the original on 2013-11-10. Retrieved 2012-12-07.
The new tissue is not the same as the tissue that was lost. After the repair process has been completed, there is a loss in the structure or function of the injured tissue. In this type of repair, it is common that granulation tissue (stromal connective tissue) proliferates to fill the defect created by the necrotic cells. The necrotic cells are then replaced by scar tissue.
- Himeno Y, Engelman RW, Good RA (June 1992). "Influence of calorie restriction on oncogene expression and DNA synthesis during liver regeneration". Proceedings of the National Academy of Sciences of the United States of America. 89 (12): 5497–501. Bibcode:1992PNAS...89.5497H. doi:10.1073/pnas.89.12.5497. PMC 49319. PMID 1608960.
- Bryant PJ, Fraser SE (May 1988). "Wound healing, cell communication, and DNA synthesis during imaginal disc regeneration in Drosophila". Developmental Biology. 127 (1): 197–208. doi:10.1016/0012-1606(88)90201-1. PMID 2452103.
- Brockes JP, Kumar A (2008). "Comparative aspects of animal regeneration". Annual Review of Cell and Developmental Biology. 24: 525–49. doi:10.1146/annurev.cellbio.24.110707.175336. PMID 18598212.
- Sánchez Alvarado A (June 2000). "Regeneration in the metazoans: why does it happen?" (PDF). BioEssays. 22 (6): 578–90. doi:10.1002/(SICI)1521-1878(200006)22:6<578::AID-BIES11>3.0.CO;2-#. PMID 10842312.
- Reddien PW, Sánchez Alvarado A (2004). "Fundamentals of planarian regeneration". Annual Review of Cell and Developmental Biology. 20: 725–57. doi:10.1146/annurev.cellbio.20.010403.095114. PMID 15473858.
- Campbell NA (1996). Biology (4th ed.). California: The Benjamin Cummings Publishing Company, Inc. p. 1206. ISBN 978-0-8053-1940-8.
- Wilkie IC (December 2001). "Autotomy as a prelude to regeneration in echinoderms". Microscopy Research and Technique. 55 (6): 369–96. doi:10.1002/jemt.1185. PMID 11782069.
- Maiorana VC (1977). "Tail autotomy, functional conflicts and their resolution by a salamander". Nature. 2265 (5594): 533–535. Bibcode:1977Natur.265..533M. doi:10.1038/265533a0.
- Maginnis TL (2006). "The costs of autotomy and regeneration in animals: a review and framework for future research". Behavioral Ecology. 7 (5): 857–872. doi:10.1093/beheco/arl010.
- "UCSB Science Line". scienceline.ucsb.edu. Retrieved 2015-11-02.
- Dietze MC, Clark JS (2008). "Changing the gap dynamics paradigm: Vegetative regenerative control on forest response to disturbance" (PDF). Ecological Monographs. 78 (3): 331–347. doi:10.1890/07-0271.1.
- Bailey J, Covington WW (2002). "Evaluation ponderosa pine regeneration rates following ecological restoration treatments in northern Arizona, USA" (PDF). Forest Ecology and Management. 155: 271–278. doi:10.1016/S0378-1127(01)00564-3.
- Fu SY, Gordon T (1997). "The cellular and molecular basis of peripheral nerve regeneration". Molecular Neurobiology. 14 (1–2): 67–116. doi:10.1007/BF02740621. PMID 9170101.
- Akimenko MA, Johnson SL, Westerfield M, Ekker M (February 1995). "Differential induction of four msx homeobox genes during fin development and regeneration in zebrafish" (PDF). Development. 121 (2): 347–57. PMID 7768177.
- Sánchez Alvarado A, Tsonis PA (November 2006). "Bridging the regeneration gap: genetic insights from diverse animal models" (PDF). Nature Reviews. Genetics. 7 (11): 873–84. doi:10.1038/nrg1923. PMID 17047686.
- Kumar A, Godwin JW, Gates PB, Garza-Garcia AA, Brockes JP (November 2007). "Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate". Science. 318 (5851): 772–7. Bibcode:2007Sci...318..772K. doi:10.1126/science.1147710. PMC 2696928. PMID 17975060.
- Skinner DM (1985). "Molting and Regneration". In Bliss DE, Mantel LH. Integument, Pigments, and Hormonal Processes. 9. Academic Press. pp. 46–146. ISBN 978-0-323-13922-9.
- Seifert AW, Monaghan JR, Smith MD, Pasch B, Stier AC, Michonneau F, Maden M (May 2012). "The influence of fundamental traits on mechanisms controlling appendage regeneration". Biological Reviews of the Cambridge Philosophical Society. 87 (2): 330–45. doi:10.1111/j.1469-185X.2011.00199.x. PMID 21929739.
- Travis DF (February 1955). "The Molting Cycle of the Spiny Lobster, Panulirus argus Latreille. II. Pre-Ecdysial Histological and Histochemical Changes in the Hepatopancreas and Integumental Tissues". Biological Bulletin. 108 (1): 88–112. doi:10.2307/1538400. JSTOR 1538400.
- Das S (November 2015). "Morphological, Molecular, and Hormonal Basis of Limb Regeneration across Pancrustacea". Integrative and Comparative Biology. 55 (5): 869–77. doi:10.1093/icb/icv101. PMID 26296354.
- Hamada Y, Bando T, Nakamura T, Ishimaru Y, Mito T, Noji S, Tomioka K, Ohuchi H (September 2015). "Leg regeneration is epigenetically regulated by histone H3K27 methylation in the cricket Gryllus bimaculatus". Development. 142 (17): 2916–27. doi:10.1242/dev.122598. PMID 26253405.
- Nisani Z, Dunbar SG, Hayes WK (June 2007). "Cost of venom regeneration in Parabuthus transvaalicus (Arachnida: Buthidae)". Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology. 147 (2): 509–13. doi:10.1016/j.cbpa.2007.01.027. PMID 17344080.
- Bely AE (August 2006). "Distribution of segment regeneration ability in the Annelida". Integrative and Comparative Biology. 46 (4): 508–18. doi:10.1093/icb/icj051. PMID 21672762.
- Hill SD (December 1972). "Caudal regeneration in the absence of a brain in two species of sedentary polychaetes". Journal of Embryology and Experimental Morphology. 28 (3): 667–80. PMID 4655324.
- Giani VC, Yamaguchi E, Boyle MJ, Seaver EC (May 2011). "Somatic and germline expression of piwi during development and regeneration in the marine polychaete annelid Capitella teleta". EvoDevo. 2: 10. doi:10.1186/2041-9139-2-10. PMC 3113731. PMID 21545709.
- Zoran MJ (2001). Regeneration in Annelids. John Wiley & Sons, Ltd. doi:10.1002/9780470015902.a0022103. ISBN 978-0-470-01590-2.
- Bely AE (October 2014). "Early events in annelid regeneration: a cellular perspective". Integrative and Comparative Biology. 54 (4): 688–99. doi:10.1093/icb/icu109. PMID 25122930.
- Candia Carnevali MD, Bonasoro F, Patruno M, Thorndyke MC (October 1998). "Cellular and molecular mechanisms of arm regeneration in crinoid echinoderms: the potential of arm explants". Development Genes and Evolution. 208 (8): 421–30. doi:10.1007/s004270050199. PMID 9799422.
- San Miguel-Ruiz JE, Maldonado-Soto AR, García-Arrarás JE (January 2009). "Regeneration of the radial nerve cord in the sea cucumber Holothuria glaberrima". BMC Developmental Biology. 9: 3. doi:10.1186/1471-213X-9-3. PMC 2640377. PMID 19126208.
- Patruno M, Thorndyke MC, Candia Carnevali MD, Bonasoro F, Beesley PW (March 2001). "Growth factors, heat-shock proteins and regeneration in echinoderms". The Journal of Experimental Biology. 204 (Pt 5): 843–8. PMID 11171408.
- Morgan TH (1900). "Regeneration in Planarians". Archiv für Entwicklungsmechanik der Organismen. 10 (1): 58–119. doi:10.1007/BF02156347.
- García-Arrarás JE, Greenberg MJ (December 2001). "Visceral regeneration in holothurians". Microscopy Research and Technique. 55 (6): 438–51. doi:10.1002/jemt.1189. PMID 11782073.
- Sánchez Alvarado A, Newmark PA (1998). "The use of planarians to dissect the molecular basis of metazoan regeneration". Wound Repair and Regeneration. 6 (4): 413–20. PMID 9824561.
- Montgomery JR, Coward SJ (July 1974). "On the minimal size of a planarian capable of regeneration". Transactions of the American Microscopical Society. 93 (3): 386–91. PMID 4853459.
- Elliott SA, Sánchez Alvarado A (2012). "The history and enduring contributions of planarians to the study of animal regeneration". Wiley Interdisciplinary Reviews: Developmental Biology. 2 (3): 301–26. doi:10.1002/wdev.82. PMC 3694279. PMID 23799578.
- Wagner DE, Wang IE, Reddien PW (May 2011). "Clonogenic neoblasts are pluripotent adult stem cells that underlie planarian regeneration". Science. 332 (6031): 811–6. Bibcode:2011Sci...332..811W. doi:10.1126/science.1203983. PMC 3338249. PMID 21566185.
- Reddien PW, Sánchez Alvarado A (2004). "Fundamentals of planarian regeneration". Annual Review of Cell and Developmental Biology. 20: 725–57. doi:10.1146/annurev.cellbio.20.010403.095114. PMID 15473858.
- Brockes JP, Kumar A, Velloso CP (2001). "Regeneration as an evolutionary variable". Journal of Anatomy. 199 (Pt 1-2): 3–11. PMC 1594962. PMID 11523827.
- Brockes JP, Kumar A (August 2002). "Plasticity and reprogramming of differentiated cells in amphibian regeneration". Nature Reviews. Molecular Cell Biology. 3 (8): 566–74. doi:10.1038/nrm881. PMID 12154368.
- Iten LE, Bryant SV (December 1973). "Forelimb regeneration from different levels of amputation in the newt, Notophthalmus viridescens: Length, rate, and stages". Wilhelm Roux' Archiv Fur Entwicklungsmechanik Der Organismen. 173 (4): 263–282. doi:10.1007/BF00575834. PMID 28304797.
- Endo T, Bryant SV, Gardiner DM (June 2004). "A stepwise model system for limb regeneration". Developmental Biology. 270 (1): 135–45. doi:10.1016/j.ydbio.2004.02.016. PMID 15136146.
- Satoh A, Bryant SV, Gardiner DM (June 2012). "Nerve signaling regulates basal keratinocyte proliferation in the blastema apical epithelial cap in the axolotl (Ambystoma mexicanum)". Developmental Biology. 366 (2): 374–81. doi:10.1016/j.ydbio.2012.03.022. PMID 22537500.
- Christensen RN, Tassava RA (February 2000). "Apical epithelial cap morphology and fibronectin gene expression in regenerating axolotl limbs". Developmental Dynamics. 217 (2): 216–24. doi:10.1002/(sici)1097-0177(200002)217:2<216::aid-dvdy8>3.0.co;2-8. PMID 10706145.
- Bryant SV, Endo T, Gardiner DM (2002). "Vertebrate limb regeneration and the origin of limb stem cells". The International Journal of Developmental Biology. 46 (7): 887–96. PMID 12455626.
- Mullen LM, Bryant SV, Torok MA, Blumberg B, Gardiner DM (November 1996). "Nerve dependency of regeneration: the role of Distal-less and FGF signaling in amphibian limb regeneration". Development. 122 (11): 3487–97. PMID 8951064.
- Souppouris A (May 2013). "Scientists identify cell that could hold the secret to limb regeneration". the verge.com.
Macrophages are a type of repairing cell that devour dead cells and pathogens, and trigger other immune cells to respond to pathogens.
- Godwin JW, Pinto AR, Rosenthal NA (June 2013). "Macrophages are required for adult salamander limb regeneration". Proceedings of the National Academy of Sciences of the United States of America. 110 (23): 9415–20. Bibcode:2013PNAS..110.9415G. doi:10.1073/pnas.1300290110. PMC 3677454. PMID 23690624. Lay summary – ScienceDaily.
- Voss SR, Muzinic L, Zimmerman G (2018). "Sal-Site". Ambystoma.org.
- Liversage RA, Anderson M, Korneluk RG (February 2005). "Regenerative response of amputated forelimbs of Xenopus laevis froglets to partial denervation". Journal of Morphology. 191: 131–144. doi:10.1002/jmor.1051910204.
- Reya T, Clevers H (April 2005). "Wnt signalling in stem cells and cancer". Nature. 434 (7035): 843–50. Bibcode:2005Natur.434..843R. doi:10.1038/nature03319. PMID 15829953.
- Kragl M, Knapp D, Nacu E, Khattak S, Maden M, Epperlein HH, Tanaka EM (July 2009). "Cells keep a memory of their tissue origin during axolotl limb regeneration". Nature. 460 (7251): 60–5. Bibcode:2009Natur.460...60K. doi:10.1038/nature08152. PMID 19571878.
- Muneoka K, Fox WF, Bryant SV (July 1986). "Cellular contribution from dermis and cartilage to the regenerating limb blastema in axolotls". Developmental Biology. 116 (1): 256–60. doi:10.1016/0012-1606(86)90062-x. PMID 3732605.
- Bryant SV, Endo T, Gardiner DM (2002). "Vertebrate limb regeneration and the origin of limb stem cells". The International Journal of Developmental Biology. 46 (7): 887–96. PMID 12455626.
- Bosch TC (March 2007). "Why polyps regenerate and we don't: towards a cellular and molecular framework for Hydra regeneration". Developmental Biology. Elsevier. 303 (2): 421–33. doi:10.1016/j.ydbio.2006.12.012. PMID 17234176.
- Wenger Y, Buzgariu W, Reiter S, Galliot B (August 2014). "Injury-induced immune responses in Hydra". Seminars in Immunology. Elsevier. 26 (4): 277–94. doi:10.1016/j.smim.2014.06.004.
- Buzgariu W, Crescenzi M, Galliot B (2014). Science Direct. "Robust G2 pausing of adult stem cells in Hydra". Differentiation; Research in Biological Diversity. Elsevier. 87 (1–2): 83–99. doi:10.1016/j.diff.2014.03.001.
- Morgan TH (1901). Regeneration. Columbia University Biological Series. 7. New York: The MacMillan Company.
- Agata K, Saito Y, Nakajima E (February 2007). "Unifying principles of regeneration I: Epimorphosis versus morphallaxis". Development, Growth & Differentiation. 49 (2): 73–8. doi:10.1111/j.1440-169X.2007.00919.x. PMID 17335428.
- Vorontsova MA, Liosner LD (1960). Billet F, ed. Asexual Reproduction and Regeneration. Translated by Allen PM. London: Pergamon Press. pp. 367–371.
- Sidorova VF (July 1962). "Liver regeneration in birds". Biulleten' Eksperimental'noi Biologii I Meditsiny. 52 (6): 1426–9. doi:10.1007/BF00785312. PMID 14039265.
- Cotanche DA, Lee KH, Stone JS, Picard DA (January 1994). "Hair cell regeneration in the bird cochlea following noise damage or ototoxic drug damage". Anatomy and Embryology. 189 (1): 1–18. doi:10.1007/BF00193125. PMID 8192233.
- Coleman CM (September 2008). "Chicken embryo as a model for regenerative medicine". Birth Defects Research. Part C, Embryo Today. 84 (3): 245–56. doi:10.1002/bdrc.20133. PMID 18773459.
- Özpolat BD, Zapata M, Daniel Frugé J, Coote J, Lee J, Muneoka K, Anderson R (December 2012). "Regeneration of the elbow joint in the developing chick embryo recapitulates development". Developmental Biology. 372 (2): 229–38. doi:10.1016/j.ydbio.2012.09.020. PMC 3501998. PMID 23036343.
- Hosker A (1936). "Regeneration of Feathers after Thyroid Feeding". Journal of Experimental Biology. 13: 344–351.
- Kresie L (April 2001). "Artificial blood: an update on current red cell and platelet substitutes". Proceedings. 14 (2): 158–61. PMC 1291332. PMID 16369608.
- Li C, Pearson A, McMahon C (2013). "Morphogenetic mechanisms in the cyclic regeneration of hair follicles and deer antlers from stem cells". BioMed Research International. 2013: 643601. doi:10.1155/2013/643601. PMC 3870647. PMID 24383056.
- Price J, Allen S (May 2004). "Exploring the mechanisms regulating regeneration of deer antlers". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 359 (1445): 809–22. doi:10.1098/rstb.2004.1471. PMC 1693364. PMID 15293809.
- Fernando WA, Leininger E, Simkin J, Li N, Malcom CA, Sathyamoorthi S, Han M, Muneoka K (February 2011). "Wound healing and blastema formation in regenerating digit tips of adult mice". Developmental Biology. 350 (2): 301–10. doi:10.1016/j.ydbio.2010.11.035. PMC 3031655. PMID 21145316.
- Seifert AW, Kiama SG, Seifert MG, Goheen JR, Palmer TM, Maden M (September 2012). "Skin shedding and tissue regeneration in African spiny mice (Acomys)". Nature. 489 (7417): 561–5. Bibcode:2012Natur.489..561S. doi:10.1038/nature11499. PMC 3480082. PMID 23018966.
- Gawriluk TR, Simkin J, Thompson KL, Biswas SK, Clare-Salzler Z, Kimani JM, Kiama SG, Smith JJ, Ezenwa VO, Seifert AW (April 2016). "Comparative analysis of ear-hole closure identifies epimorphic regeneration as a discrete trait in mammals". Nature Communications. 7: 11164. Bibcode:2016NatCo...711164G. doi:10.1038/ncomms11164. PMC 4848467. PMID 27109826.
- Matias Santos D, Rita AM, Casanellas I, Brito Ova A, Araújo IM, Power D, Tiscornia G (February 2016). "Ear wound regeneration in the African spiny mouse Acomys cahirinus". Regeneration. 3 (1): 52–61. doi:10.1002/reg2.50. PMC 4857749. PMID 27499879.
- Xu K (July 2013). "Humans' Ability To Regenerate Damaged Organs Is At Our Fingertips". Business Insider.
- Becker RO (January 1972). "Stimulation of partial limb regeneration in rats". Nature. 235 (5333): 109–11. Bibcode:1972Natur.235..109B. doi:10.1038/235109a0. PMID 4550399.
- Becker RO, Spadaro JA (May 1972). "Electrical stimulation of partial limb regeneration in mammals". Bulletin of the New York Academy of Medicine. 48 (4): 627–41. PMC 1806700. PMID 4503923.
- Masinde G, Li X, Baylink DJ, Nguyen B, Mohan S (April 2005). "Isolation of wound healing/regeneration genes using restrictive fragment differential display-PCR in MRL/MPJ and C57BL/6 mice". Biochemical and Biophysical Research Communications. 330 (1): 117–22. doi:10.1016/j.bbrc.2005.02.143. PMID 15781240.
- Hayashi ML, Rao BS, Seo JS, Choi HS, Dolan BM, Choi SY, Chattarji S, Tonegawa S (July 2007). "Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice". Proceedings of the National Academy of Sciences of the United States of America. 104 (27): 11489–94. Bibcode:2007PNAS..10411489H. doi:10.1073/pnas.0705003104. PMC 1899186. PMID 17592139.
- Bedelbaeva K, Snyder A, Gourevitch D, Clark L, Zhang XM, Leferovich J, Cheverud JM, Lieberman P, Heber-Katz E (March 2010). "Lack of p21 expression links cell cycle control and appendage regeneration in mice". Proceedings of the National Academy of Sciences of the United States of America. 107 (13): 5845–50. Bibcode:2010PNAS..107.5845B. doi:10.1073/pnas.1000830107. PMC 2851923. PMID 20231440. Lay summary – PhysOrg.com.
- Humans Could Regenerate Tissue Like Newts By Switching Off a Single Gene
- Abdullah I, Lepore JJ, Epstein JA, Parmacek MS, Gruber PJ (March–April 2005). "MRL mice fail to heal the heart in response to ischemia-reperfusion injury". Wound Repair and Regeneration. 13 (2): 205–8. doi:10.1111/j.1067-1927.2005.130212.x. PMID 15828946.
- Min S, Wang SW, Orr W (2006). "Graphic general pathology: 2.2 complete regeneration:". Pathology. pathol.med.stu.edu.cn. Archived from the original on 2012-12-07. Retrieved 2013-11-10.
After the repair process has been completed, the structure and function of the injured tissue are completely normal. This type of regeneration is common in physiological situations. Examples of physiological regeneration are the continual replacement of cells of the skin and repair of the endometrium after menstruation. Complete regeneration can occur in pathological situations in tissues that have good regenerative capacity.
- Mohammadi D (4 October 2014). "Bioengineered organs: The story so far…". The Guardian. Retrieved 9 March 2015.
- Carlson BM (2007). Principles of Regenerative Biology. Academic Press. pp. 25–26. ISBN 978-0-12-369439-3.
- Ferenczy A, Bertrand G, Gelfand MM (April 1979). "Proliferation kinetics of human endometrium during the normal menstrual cycle". American Journal of Obstetrics and Gynecology. 133 (8): 859–67. doi:10.1016/0002-9378(79)90302-8. PMID 434029.
- Michalopoulos GK, DeFrances MC (April 1997). "Liver regeneration". Science. 276 (5309): 60–6. doi:10.1126/science.276.5309.60. PMC 2701258. PMID 9082986.
- Taub R (October 2004). "Liver regeneration: from myth to mechanism". Nature Reviews. Molecular Cell Biology. 5 (10): 836–47. doi:10.1038/nrm1489. PMID 15459664.
- Kawasaki S, Makuuchi M, Ishizone S, Matsunami H, Terada M, Kawarazaki H (March 1992). "Liver regeneration in recipients and donors after transplantation". Lancet. 339 (8793): 580–1. doi:10.1016/0140-6736(92)90867-3. PMID 1347095.
- Vlahopoulos SA (August 2017). "Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode". Cancer Biology & Medicine. 14 (3): 254–270. doi:10.20892/j.issn.2095-3941.2017.0029. PMC 5570602. PMID 28884042.
- Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Boström E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, Frisén J (June 2013). "Dynamics of hippocampal neurogenesis in adult humans". Cell. 153 (6): 1219–1227. doi:10.1016/j.cell.2013.05.002. PMC 4394608. PMID 23746839.
- Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisén J (April 2009). "Evidence for cardiomyocyte renewal in humans". Science. 324 (5923): 98–102. Bibcode:2009Sci...324...98B. doi:10.1126/science.1164680. PMC 2991140. PMID 19342590.
- Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, Anversa P (June 2001). "Evidence that human cardiac myocytes divide after myocardial infarction". The New England Journal of Medicine. 344 (23): 1750–7. doi:10.1056/NEJM200106073442303. PMID 11396441.
- McKim LH (May 1932). "REGENERATION OF THE DISTAL PHALANX". Canadian Medical Association Journal. 26 (5): 549–50. PMC 402335. PMID 20318716.
- Muneoka K, Allan CH, Yang X, Lee J, Han M (December 2008). "Mammalian regeneration and regenerative medicine". Birth Defects Research. Part C, Embryo Today. 84 (4): 265–80. doi:10.1002/bdrc.20137. PMID 19067422.
- Philip SJ, Kumar RJ, Menon KV (October 2005). "Morphological study of rib regeneration following costectomy in adolescent idiopathic scoliosis". European Spine Journal. 14 (8): 772–6. doi:10.1007/s00586-005-0949-8. PMC 3489251. PMID 16047208.
- Alibardi L (2010). "Regeneration in Reptiles and Its Position Among Vertebrates". Morphological and Cellular Aspects of Tail and Limb Regeneration in Lizards a Model System with Implications for Tissue Regeneration in Mammals. Heidelberg: Springer.
- McLean KE, Vickaryous MK (August 2011). "A novel amniote model of epimorphic regeneration: the leopard gecko, Eublepharis macularius". BMC Developmental Biology. 11 (1): 50. doi:10.1186/1471-213x-11-50. PMID 21846350.
- Bellairs A, Bryant S (1985). "Autonomy and Regeneration in Reptiles". In Gans C, Billet F. Biology of the Reptilia. 15. New York: John Wiley and Sons. pp. 301–410.
- Brazaitis P (July 31, 1981). "Maxillary Regeneration in a Marsh Crocodile, Crocodylus palustris". Journal of Herpetology. 15 (3): 360–362. doi:10.2307/1563441.
- Font E, Desfilis E, Pérez-Cañellas MM, García-Verdugo JM (2001). "Neurogenesis and neuronal regeneration in the adult reptilian brain". Brain, Behavior and Evolution. 58 (5): 276–95. doi:10.1159/000057570.
- Vickaryous M (2014). "Vickaryous Lab: Regeneration - Evolution - Development". Department of Biomedical Sciences, University of Guelph.
- Sun Y, Ripps H (November 1992). "Rhodopsin regeneration in the normal and in the detached/replaced retina of the skate". Experimental Eye Research. 55 (5): 679–89. doi:10.1016/0014-4835(92)90173-p. PMID 1478278.
- Lu C, Zhang J, Nie Z, Chen J, Zhang W, Ren X, Yu W, Liu L, Jiang C, Zhang Y, Guo J, Wu W, Shu J, Lv Z (2013). "Study of microRNAs related to the liver regeneration of the whitespotted bamboo shark, Chiloscyllium plagiosum". BioMed Research International. 2013: 795676. doi:10.1155/2013/795676.
- Reif W (June 1978). "Wound Healing in Sharks". Zoomorphology. 90 (2): 101–111. doi:10.1007/bf02568678.
- Tanaka EM (October 2003). "Cell differentiation and cell fate during urodele tail and limb regeneration". Current Opinion in Genetics & Development. 13 (5): 497–501. doi:10.1016/j.gde.2003.08.003. PMID 14550415.
- Nye HL, Cameron JA, Chernoff EA, Stocum DL (February 2003). "Regeneration of the urodele limb: a review". Developmental Dynamics. 226 (2): 280–94. doi:10.1002/dvdy.10236. PMID 12557206.
- Yu H, Mohan S, Masinde GL, Baylink DJ (December 2005). "Mapping the dominant wound healing and soft tissue regeneration QTL in MRL x CAST". Mammalian Genome. 16 (12): 918–24. doi:10.1007/s00335-005-0077-0. PMID 16341671.
- Gardiner DM, Blumberg B, Komine Y, Bryant SV (June 1995). "Regulation of HoxA expression in developing and regenerating axolotl limbs". Development. 121 (6): 1731–41. PMID 7600989.
- Torok MA, Gardiner DM, Shubin NH, Bryant SV (August 1998). "Expression of HoxD genes in developing and regenerating axolotl limbs". Developmental Biology. 200 (2): 225–33. doi:10.1006/dbio.1998.8956. PMID 9705229.
- 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 (August 2004). "From biomedicine to natural history research: EST resources for ambystomatid salamanders". BMC Genomics. 5 (1): 54. doi:10.1186/1471-2164-5-54. PMC 509418. PMID 15310388.
- Andrews W (March 23, 2008). "Medicine's Cutting Edge: Re-Growing Organs". Sunday Morning. CBS News.