regeneration (biology)

{{Main|Regeneration (ecology)}}

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.{{cite journal | doi=10.1890/07-0271.1 |vauthors=Dietze MC, Clark JS | title=Changing the gap dynamics paradigm: Vegetative regenerative control on forest response to disturbance | journal=Ecological Monographs | volume=78 | issue=3 | pages=331–347 | url=http://coweeta.uga.edu/publications/10300.pdf | year=2008 | bibcode=2008EcoM...78..331D | access-date=2010-12-15 | archive-date=2010-06-10 | archive-url=https://web.archive.org/web/20100610074913/http://coweeta.uga.edu/publications/10300.pdf }}{{cite journal | doi=10.1016/S0378-1127(01)00564-3 |vauthors=Bailey J, Covington WW | title=Evaluation ponderosa pine regeneration rates following ecological restoration treatments in northern Arizona, USA | journal=Forest Ecology and Management | volume=155 | issue=1–3 | pages=271–278 | url=http://library.eri.nau.edu/gsdl/collect/erilibra/index/assoc/HASH0e9a.dir/doc.pdf | year=2002 |bibcode=2002ForEM.155..271B | access-date=2011-06-25 | archive-date=2013-11-11 | archive-url=https://web.archive.org/web/20131111153241/http://library.eri.nau.edu/gsdl/collect/erilibra/index/assoc/HASH0e9a.dir/doc.pdf }}

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.{{cite journal | vauthors = Fu SY, Gordon T | title = The cellular and molecular basis of peripheral nerve regeneration | journal = Molecular Neurobiology | volume = 14 | issue = 1–2 | pages = 67–116 | year = 1997 | pmid = 9170101 | doi = 10.1007/BF02740621 | s2cid = 13045638 }} 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.{{cite journal | vauthors = Akimenko MA, Johnson SL, Westerfield M, Ekker M | title = Differential induction of four msx homeobox genes during fin development and regeneration in zebrafish | journal = Development | volume = 121 | issue = 2 | pages = 347–57 | date = February 1995 | doi = 10.1242/dev.121.2.347 | pmid = 7768177 | url = http://dev.biologists.org/content/121/2/347.full.pdf }}

"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."{{cite journal | vauthors = Sánchez Alvarado A, Tsonis PA | title = Bridging the regeneration gap: genetic insights from diverse animal models | journal = Nature Reviews Genetics | volume = 7 | issue = 11 | pages = 873–84 | date = November 2006 | pmid = 17047686 | doi = 10.1038/nrg1923 | s2cid = 2978615 | url = http://planaria.neuro.utah.edu/publications/NRG2006.pdf | access-date = 2010-12-16 | archive-date = 2013-11-10 | archive-url = https://web.archive.org/web/20131110103049/http://planaria.neuro.utah.edu/publications/NRG2006.pdf }}{{rp|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".{{cite journal | vauthors = Kumar A, Godwin JW, Gates PB, Garza-Garcia AA, Brockes JP | title = Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate | journal = Science | volume = 318 | issue = 5851 | pages = 772–7 | date = November 2007 | pmid = 17975060 | pmc = 2696928 | doi = 10.1126/science.1147710 | bibcode = 2007Sci...318..772K }} 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.

Many arthropods can regenerate limbs and other appendages following either injury or autotomy.{{cite book | vauthors = Skinner DM | chapter = Molting and Regneration | veditors = Bliss DE, Mantel LH | title = Integument, Pigments, and Hormonal Processes | date = 1985 | volume = 9 | chapter-url = https://books.google.com/books?id=JG1lh--v1sYC | publisher = Academic Press | isbn = 978-0-323-13922-9 | pages = 46–146 }} Regeneration capacity is constrained by the developmental stage and ability to molt.{{cn|date=November 2024}}

Crustaceans, which continually molt, can regenerate throughout their lifetimes.{{cite journal | vauthors = Seifert AW, Monaghan JR, Smith MD, Pasch B, Stier AC, Michonneau F, Maden M | title = The influence of fundamental traits on mechanisms controlling appendage regeneration | journal = Biological Reviews of the Cambridge Philosophical Society | volume = 87 | issue = 2 | pages = 330–45 | date = May 2012 | pmid = 21929739 | doi = 10.1111/j.1469-185X.2011.00199.x | s2cid = 22877405 }} While molting cycles are generally hormonally regulated, limb amputation induces premature molting.{{Cite journal|title = The Molting Cycle of the Spiny Lobster, Panulirus argus Latreille. II. Pre-Ecdysial Histological and Histochemical Changes in the Hepatopancreas and Integumental Tissues | journal = Biological Bulletin|date = February 1955 | pages = 88–112 | volume = 108|issue = 1 | doi = 10.2307/1538400 | first = Dorothy F. | last = Travis | name-list-style = vanc | jstor=1538400 | url = https://www.biodiversitylibrary.org/part/20381}}

Hemimetabolous insects such as crickets can regenerate limbs as nymphs, before their final molt.{{Citation |last1=Mito |first1=Taro |title=Cricket: The third domesticated insect |date=2022 |url=https://linkinghub.elsevier.com/retrieve/pii/S0070215322000096 |journal=Current Topics in Developmental Biology |volume=147 |pages=291–306 |publisher=Elsevier |language=en |doi=10.1016/bs.ctdb.2022.02.003 |isbn=978-0-12-820154-1 |access-date=2022-06-08 |last2=Ishimaru |first2=Yoshiyasu |last3=Watanabe |first3=Takahito |last4=Nakamura |first4=Taro |last5=Ylla |first5=Guillem |last6=Noji |first6=Sumihare |last7=Extavour |first7=Cassandra G.|pmid=35337452 }}

Holometabolous insects can regenerate appendages as larvae prior to the final molt and metamorphosis. Beetle larvae, for example, can regenerate amputated limbs. Fruit fly larvae do not have limbs but can regenerate their appendage primordia, imaginal discs.{{Cite journal |last1=Fox |first1=Donald T. |last2=Cohen |first2=Erez |last3=Smith-Bolton |first3=Rachel |date=2020-04-01 |title=Model systems for regeneration: Drosophila |url=https://journals.biologists.com/dev/article/147/7/dev173781/223043/Model-systems-for-regeneration-Drosophila |journal=Development |language=en |volume=147 |issue=7 |pages=dev173781 |doi=10.1242/dev.173781 |issn=1477-9129 |pmc=7157589 |pmid=32253254}} In both systems, the regrowth of the new tissue delays pupation.{{cite web |last=Roche |first=John P. |date=September 22, 2020 |title=Limb Regeneration in Lady Beetles: Product of Selection or Developmental Byproduct? |url=https://entomologytoday.org/2020/09/22/limb-regeneration-lady-beetles-product-selection-developmental-byproduct/ |access-date=September 23, 2020 |website=Entomology Today |publisher=Entomological Society of America}}

Mechanisms underlying appendage limb regeneration in insects and crustaceans are highly conserved.{{cite journal |vauthors=Das S |date=November 2015 |title=Morphological, Molecular, and Hormonal Basis of Limb Regeneration across Pancrustacea |journal=Integrative and Comparative Biology |volume=55 |issue=5 |pages=869–77 |doi=10.1093/icb/icv101 |pmid=26296354 |doi-access=free}} During limb regeneration species in both taxa form a blastema that proliferates and grows to repattern the missing tissue.{{cite journal |vauthors=Hamada Y, Bando T, Nakamura T, Ishimaru Y, Mito T, Noji S, Tomioka K, Ohuchi H |date=September 2015 |title=Leg regeneration is epigenetically regulated by histone H3K27 methylation in the cricket Gryllus bimaculatus |journal=Development |volume=142 |issue=17 |pages=2916–27 |doi=10.1242/dev.122598 |pmid=26253405 |doi-access=free}}

Arachnids, including scorpions, are known to regenerate their venom, although the content of the regenerated venom is different from the original venom during its regeneration, as the venom volume is replaced before the active proteins are all replenished.{{cite journal | vauthors = Nisani Z, Dunbar SG, Hayes WK | title = Cost of venom regeneration in Parabuthus transvaalicus (Arachnida: Buthidae) | journal = Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology | volume = 147 | issue = 2 | pages = 509–13 | date = June 2007 | pmid = 17344080 | doi = 10.1016/j.cbpa.2007.01.027 }}

The fruit fly Drosophila melanogaster is a useful model organism to understand the molecular mechanisms that control regeneration, especially gut and germline regeneration. In these tissues, resident stem cells continually renew lost cells. The Hippo signaling pathway was discovered in flies and was found to be required for midgut regeneration. Later, this conserved signaling pathway was also found to be essential for regeneration of many mammalian tissues, including heart, liver, skin, and lung, and intestine.{{Cite journal |last1=Moya |first1=Iván M |last2=Halder |first2=Georg |date=2016-12-01 |title=The Hippo pathway in cellular reprogramming and regeneration of different organs |url=https://www.sciencedirect.com/science/article/pii/S095506741630134X |journal=Current Opinion in Cell Biology |series=Differentiation and disease |language=en |volume=43 |pages=62–68 |doi=10.1016/j.ceb.2016.08.004 |pmid=27592171 |issn=0955-0674}}

Many annelids (segmented worms) are capable of regeneration.{{cite journal | vauthors = Bely AE | title = Distribution of segment regeneration ability in the Annelida | journal = Integrative and Comparative Biology | volume = 46 | issue = 4 | pages = 508–18 | date = August 2006 | pmid = 21672762 | doi = 10.1093/icb/icj051 | doi-access = free }} For example, Chaetopterus variopedatus and Branchiomma nigromaculata can regenerate both anterior and posterior body parts after latitudinal bisection.{{cite journal | vauthors = Hill SD | title = Caudal regeneration in the absence of a brain in two species of sedentary polychaetes | journal = Journal of Embryology and Experimental Morphology | volume = 28 | issue = 3 | pages = 667–80 | date = December 1972 | pmid = 4655324 }} The relationship between somatic and germline stem cell regeneration has been studied at the molecular level in the annelid Capitella teleta.{{cite journal | vauthors = Giani VC, Yamaguchi E, Boyle MJ, Seaver EC | title = Somatic and germline expression of piwi during development and regeneration in the marine polychaete annelid Capitella teleta | journal = EvoDevo | volume = 2 | page = 10 | date = May 2011 | pmid = 21545709 | pmc = 3113731 | doi = 10.1186/2041-9139-2-10 | doi-access = free }} Leeches, however, appear incapable of segmental regeneration.{{Cite book|chapter = Regeneration in Annelids | publisher = John Wiley & Sons, Ltd|date = 2001 | isbn = 978-0-470-01590-2 | doi = 10.1002/9780470015902.a0022103 | first = Mark J | last = Zoran | name-list-style = vanc | title = Encyclopedia of Life Sciences}} 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.{{cite journal | vauthors = Bely AE | title = Early events in annelid regeneration: a cellular perspective | journal = Integrative and Comparative Biology | volume = 54 | issue = 4 | pages = 688–99 | date = October 2014 | pmid = 25122930 | doi = 10.1093/icb/icu109 | doi-access = free }} 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.{{cn|date=November 2024}}

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.{{cite journal | vauthors = Candia Carnevali MD, Bonasoro F, Patruno M, Thorndyke MC | title = Cellular and molecular mechanisms of arm regeneration in crinoid echinoderms: the potential of arm explants | journal = Development Genes and Evolution | volume = 208 | issue = 8 | pages = 421–30 | date = October 1998 | pmid = 9799422 | doi = 10.1007/s004270050199 | s2cid = 23560812 }} In addition to appendages, some species can regenerate internal organs and parts of their central nervous system.{{cite journal | vauthors = San Miguel-Ruiz JE, Maldonado-Soto AR, García-Arrarás JE | title = Regeneration of the radial nerve cord in the sea cucumber Holothuria glaberrima | journal = BMC Developmental Biology | volume = 9 | page = 3 | date = January 2009 | pmid = 19126208 | pmc = 2640377 | doi = 10.1186/1471-213X-9-3 | doi-access = free }} 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.{{cite journal | vauthors = Patruno M, Thorndyke MC, Candia Carnevali MD, Bonasoro F, Beesley PW | title = Growth factors, heat-shock proteins and regeneration in echinoderms | journal = The Journal of Experimental Biology | volume = 204 | issue = Pt 5 | pages = 843–8 | date = March 2001 | doi = 10.1242/jeb.204.5.843 | pmid = 11171408 | url = http://jeb.biologists.org/content/204/5/843 }} Some species must retain mouth cells 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.{{cite journal | vauthors = García-Arrarás JE, Greenberg MJ | title = Visceral regeneration in holothurians | journal = Microscopy Research and Technique | volume = 55 | issue = 6 | pages = 438–51 | date = December 2001 | pmid = 11782073 | doi = 10.1002/jemt.1189 | s2cid = 11533400 | doi-access = free }}

Regeneration research using Planarians began in the late 1800s and was popularized by T.H. Morgan at the beginning of the 20th century.{{Cite journal |title = Regeneration in Planarians | vauthors = Morgan TH | date = 1900 | journal = Archiv für Entwicklungsmechanik der Organismen | volume= 10 | issue = 1 | pages = 58–119 | doi = 10.1007/BF02156347 | hdl = 2027/hvd.32044107333064 | s2cid = 33712732 | hdl-access = free }} 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.{{cite journal | vauthors = Sánchez Alvarado A, Newmark PA | title = The use of planarians to dissect the molecular basis of metazoan regeneration | journal = Wound Repair and Regeneration | volume = 6 | issue = 4 | pages = 413–20 | year = 1998 | pmid = 9824561 | doi=10.1046/j.1524-475x.1998.60418.x| s2cid = 8085897 }} 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.{{cite journal | vauthors = Montgomery JR, Coward SJ | title = On the minimal size of a planarian capable of regeneration | journal = Transactions of the American Microscopical Society | volume = 93 | issue = 3 | pages = 386–91 | date = July 1974 | pmid = 4853459 | doi = 10.2307/3225439 | jstor = 3225439 }} After amputation, stump cells form a blastema formed from neoblasts, pluripotent cells found throughout the planarian body.{{cite journal | vauthors = Elliott SA, Sánchez Alvarado A | title = The history and enduring contributions of planarians to the study of animal regeneration | journal = Wiley Interdisciplinary Reviews: Developmental Biology | volume = 2 | issue = 3 | pages = 301–26 | year = 2012 | pmid = 23799578 | doi = 10.1002/wdev.82 | pmc = 3694279 }} 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.{{cite journal | vauthors = Wagner DE, Wang IE, Reddien PW | title = Clonogenic neoblasts are pluripotent adult stem cells that underlie planarian regeneration | journal = Science | volume = 332 | issue = 6031 | pages = 811–6 | date = May 2011 | pmid = 21566185 | doi = 10.1126/science.1203983 | pmc = 3338249 | bibcode = 2011Sci...332..811W }} 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. Although researchers have developed genetically altered axolotls, live cell imaging remains difficult due to the large size of adult axolotls. To fix this issue, they use small juvenile axolotls, focus on smaller amputations like digits, and reduce light distortion caused by refraction in water by using iodixanol, a substance that is safe for living cells and tissues. {{Cite journal |last=Masselink |first=Wouter |last2=Tanaka |first2=Elly M. |date=2021 |title=Toward whole tissue imaging of axolotl regeneration |url=https://anatomypubs.onlinelibrary.wiley.com/doi/10.1002/dvdy.282 |journal=Developmental Dynamics |language=en |volume=250 |issue=6 |pages=800–806 |doi=10.1002/dvdy.282 |issn=1097-0177 |pmc=8247021 |pmid=33336514}}The nineteenth century studies of this subject are reviewed in Holland (2021). Urodele amphibians, such as salamanders and newts, display the highest regenerative ability among tetrapods.{{cite journal | vauthors = Brockes JP, Kumar A, Velloso CP | title = Regeneration as an evolutionary variable | journal = Journal of Anatomy | volume = 199 | issue = Pt 1–2 | pages = 3–11 | date = 2001 | pmid = 11523827 | pmc = 1594962 | doi = 10.1046/j.1469-7580.2001.19910003.x}}{{citation |title=Vicenzo Colucci's 1886 memoir, Intorno alla rigenerazione degli arti e della coda nei tritoni, annotated and translated into English as: Concerning regeneration of the limbs and tail in salamanders | first=Nicholas | last=Holland | journal=The European Zoological Journal | volume=88 | year=2021| pages=837–890 | doi=10.1080/24750263.2021.1943549 | doi-access=free }} As such, they can fully regenerate their limbs, tail, jaws, and retina via epimorphic regeneration leading to functional replacement with new tissue.{{cite journal | vauthors = Brockes JP, Kumar A | title = Plasticity and reprogramming of differentiated cells in amphibian regeneration | journal = Nature Reviews Molecular Cell Biology | volume = 3 | issue = 8 | pages = 566–74 | date = August 2002 | pmid = 12154368 | doi = 10.1038/nrm881 | s2cid = 21409289 }} Salamander limb regeneration occurs in two main steps. First, the local cells dedifferentiate at the wound site into progenitor to form a blastema.{{cite journal | vauthors = Iten LE, Bryant SV | title = Forelimb regeneration from different levels of amputation in the newt, Notophthalmus viridescens: Length, rate, and stages | journal = Wilhelm Roux' Archiv für Entwicklungsmechanik der Organismen | volume = 173 | issue = 4 | pages = 263–282 | date = December 1973 | pmid = 28304797 | doi = 10.1007/BF00575834 | s2cid = 3946430 | url = https://escholarship.org/uc/item/276728qx }} Second, the blastemal cells will undergo cell proliferation, patterning, cell differentiation and tissue growth using similar genetic mechanisms that deployed during embryonic development. Ultimately, blastemal cells will generate all the cells for the new structure.

File:AxolotlBE.jpgs can regenerate a variety of structures, including their limbs.]]

After amputation, the epidermis migrates to cover the stump in 1–2 hours, forming a structure called the wound epithelium (WE).{{cite journal | vauthors = Satoh A, Bryant SV, Gardiner DM | title = Nerve signaling regulates basal keratinocyte proliferation in the blastema apical epithelial cap in the axolotl (Ambystoma mexicanum) | journal = Developmental Biology | volume = 366 | issue = 2 | pages = 374–81 | date = June 2012 | pmid = 22537500 | doi = 10.1016/j.ydbio.2012.03.022 | doi-access = free }} Epidermal cells continue to migrate over the WE, resulting in a thickened, specialized signaling center called the apical epithelial cap (AEC).{{cite journal | vauthors = Christensen RN, Tassava RA | title = Apical epithelial cap morphology and fibronectin gene expression in regenerating axolotl limbs | journal = Developmental Dynamics | volume = 217 | issue = 2 | pages = 216–24 | date = February 2000 | pmid = 10706145 | doi = 10.1002/(sici)1097-0177(200002)217:2<216::aid-dvdy8>3.0.co;2-8 | s2cid = 29415248 | doi-access = }} 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.{{cite journal | vauthors = Bryant SV, Endo T, Gardiner DM | title = Vertebrate limb regeneration and the origin of limb stem cells | journal = The International Journal of Developmental Biology | volume = 46 | issue = 7 | pages = 887–96 | year = 2002 | pmid = 12455626 }}{{cite journal | vauthors = Mullen LM, Bryant SV, Torok MA, Blumberg B, Gardiner DM | title = Nerve dependency of regeneration: the role of Distal-less and FGF signaling in amphibian limb regeneration | journal = Development | volume = 122 | issue = 11 | pages = 3487–97 | date = November 1996 | doi = 10.1242/dev.122.11.3487 | pmid = 8951064 | url = https://escholarship.org/uc/item/96k9640g }} 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,{{cite web | last = Souppouris | first = Aaron | title = Scientists identify cell that could hold the secret to limb regeneration | quote = Macrophages are a type of repairing cell that devour dead cells and pathogens, and trigger other immune cells to respond to pathogens. | work = The Verge | date = May 23, 2013 | url = https://www.theverge.com/2013/5/23/4358418/salamander-macrophages-could-aid-limb-regeneration

}} were removed, salamanders lost their ability to regenerate and formed scarred tissue instead.{{cite journal | vauthors = Godwin JW, Pinto AR, Rosenthal NA | title = Macrophages are required for adult salamander limb regeneration | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 23 | pages = 9415–20 | date = June 2013 | pmid = 23690624 | pmc = 3677454 | doi = 10.1073/pnas.1300290110 | bibcode = 2013PNAS..110.9415G | doi-access = free }}

• {{cite press release |date=May 20, 2013 |title=Do salamanders' immune systems hold the key to regeneration? |website=ScienceDaily |url=https://www.sciencedaily.com/releases/2013/05/130520163727.htm}} The axolotl salamander Ambystoma mexicanum, an organism with exceptional limb regenerative capabilities, likely undergoes epigenetic alterations in its blastema cells that enhance expression of genes involved in limb regeneration. The Axolotl has very little blood and has an excess of epidermal cells. This allows the affected area to then flourish with epidermal cells and continued gene expression allows the area to regenerate to its natural being.Min S, Whited JL. Limb blastema formation: How much do we know at a genetic and epigenetic level? J Biol Chem. 2023 Feb;299(2):102858. doi: 10.1016/j.jbc.2022.102858. Epub 2022 Dec 31. PMID 36596359; PMCID: PMC9898764

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.{{cite journal | vauthors = Endo T, Bryant SV, Gardiner DM | title = A stepwise model system for limb regeneration | journal = Developmental Biology | volume = 270 | issue = 1 | pages = 135–45 | date = June 2004 | pmid = 15136146 | doi = 10.1016/j.ydbio.2004.02.016 | s2cid = 7581434 | url = https://escholarship.org/content/qt2bz1g50v/qt2bz1g50v.pdf?t=oyzob1 }} 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.{{cite web | vauthors = Voss SR, Muzinic L, Zimmerman G | url = http://www.ambystoma.org | title = Sal-Site | work = Ambystoma.org | date = 2018 }} In 2022, a first spatiotemporal map revealed key insights about axolotl brain regeneration, also providing the interactive Axolotl Regenerative Telencephalon Interpretation via Spatiotemporal Transcriptomic Atlas.{{cite news |title=Single-cell Stereo-seq reveals new insights into axolotl brain regeneration |url=https://www.news-medical.net/news/20220906/Single-cell-Stereo-seq-reveals-new-insights-into-axolotl-brain-regeneration.aspx |access-date=19 October 2022 |work=News-Medical.net |date=6 September 2022 |language=en}}{{cite journal |last1=Wei |first1=Xiaoyu |last2=Fu |first2=Sulei |last3=Li |first3=Hanbo |last4=Liu |first4=Yang |last5=Wang |first5=Shuai |last6=Feng |first6=Weimin |last7=Yang |first7=Yunzhi |last8=Liu |first8=Xiawei |last9=Zeng |first9=Yan-Yun |last10=Cheng |first10=Mengnan |last11=Lai |first11=Yiwei |last12=Qiu |first12=Xiaojie |last13=Wu |first13=Liang |last14=Zhang |first14=Nannan |last15=Jiang |first15=Yujia |last16=Xu |first16=Jiangshan |last17=Su |first17=Xiaoshan |last18=Peng |first18=Cheng |last19=Han |first19=Lei |last20=Lou |first20=Wilson Pak-Kin |last21=Liu |first21=Chuanyu |last22=Yuan |first22=Yue |last23=Ma |first23=Kailong |last24=Yang |first24=Tao |last25=Pan |first25=Xiangyu |last26=Gao |first26=Shang |last27=Chen |first27=Ao |last28=Esteban |first28=Miguel A. |last29=Yang |first29=Huanming |last30=Wang |first30=Jian |last31=Fan |first31=Guangyi |last32=Liu |first32=Longqi |last33=Chen |first33=Liang |last34=Xu |first34=Xun |last35=Fei |first35=Ji-Feng |last36=Gu |first36=Ying |title=Single-cell Stereo-seq reveals induced progenitor cells involved in axolotl brain regeneration |journal=Science |date=2 September 2022 |volume=377 |issue=6610 |pages=eabp9444 |doi=10.1126/science.abp9444 |pmid=36048929 |s2cid=252010604 |url=https://www.science.org/doi/10.1126/science.abp9444 |language=en |issn=0036-8075|url-access=subscription}}

Anurans (frogs) can only regenerate their limbs during embryonic development.{{Cite journal | first1 = Richard A. | last1 = Liversage | first2 = Meri-Jo | last2 = Anderson | first3 = Robert G. | last3 = Korneluk | name-list-style = vanc |title = Regenerative response of amputated forelimbs of Xenopus laevis froglets to partial denervation | date = February 2005 | journal = Journal of Morphology | doi = 10.1002/jmor.1051910204 | pmid = 29921109 | volume = 191 | issue = 2 | pages = 131–144 | s2cid = 49315283 }} Reactive oxygen species (ROS) appear to be required for a regeneration response in the anuran larvae.{{cite journal | vauthors = Reya T, Clevers H | title = Wnt signalling in stem cells and cancer | journal = Nature | volume = 434 | issue = 7035 | pages = 843–50 | date = April 2005 | pmid = 15829953 | doi = 10.1038/nature03319 | bibcode = 2005Natur.434..843R | s2cid = 3645313 }} ROS production is essential to activate the Wnt signaling pathway, which has been associated with regeneration in other systems.

Once the limb skeleton has developed in frogs, regeneration does not occur (Xenopus can grow a cartilaginous spike after amputation). The adult Xenopus laevis is used as a model organism for regenerative medicine. In 2022, a cocktail of drugs and hormones (1,4-DPCA, BDNF, growth hormone, resolvin D5, and retinoic acid), in a single dose lasting 24 hours, was shown to trigger long-term leg regeneration in adult X. laevis. Instead of a single spike, a paddle-shaped growth is obtained at the end of the limb by 18 months.{{cite journal |last1=Murugan |first1=Nirosha J. |last2=Vigran |first2=Hannah J. |last3=Miller |first3=Kelsie A. |last4=Golding |first4=Annie |last5=Pham |first5=Quang L. |last6=Sperry |first6=Megan M. |last7=Rasmussen-Ivey |first7=Cody |last8=Kane |first8=Anna W. |author9-link=David L. Kaplan (engineer) |last9=Kaplan |first9=David L. |last10=Levin |first10=Michael |title=Acute multidrug delivery via a wearable bioreactor facilitates long-term limb regeneration and functional recovery in adult Xenopus laevis |journal=Science Advances |date=28 January 2022 |volume=8 |issue=4 |pages=eabj2164 |doi=10.1126/sciadv.abj2164 |pmid=35080969 |pmc=8791464 |bibcode=2022SciA....8.2164M |doi-access=free}}

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.{{cite journal | vauthors = Bosch TC | title = Why polyps regenerate and we don't: towards a cellular and molecular framework for Hydra regeneration | journal = Developmental Biology | volume = 303 | issue = 2 | pages = 421–33 | date = March 2007 | pmid = 17234176 | doi = 10.1016/j.ydbio.2006.12.012 | doi-access = free }} 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.{{cite journal | vauthors = Wenger Y, Buzgariu W, Reiter S, Galliot B | title = Injury-induced immune responses in Hydra | journal = Seminars in Immunology | volume = 26 | issue = 4 | pages = 277–94 | date = August 2014 | pmid = 25086685| doi = 10.1016/j.smim.2014.06.004 | doi-access = free }}

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.{{cite journal | vauthors = Buzgariu W, Crescenzi M, Galliot B | title = Robust G2 pausing of adult stem cells in Hydra | journal = Differentiation; Research in Biological Diversity | volume = 87 | issue = 1–2 | pages = 83–99 | date = 2014 | doi = 10.1016/j.diff.2014.03.001 | pmid = 24703763 | others = Science Direct | doi-access = free }} 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.{{cite book | vauthors = Morgan TH | year = 1901 | title = Regeneration | volume = 7 | series = Columbia University Biological Series | publisher = The MacMillan Company | location = New York | url = https://archive.org/details/regeneration00morggoog }}{{cite journal | vauthors = Agata K, Saito Y, Nakajima E | title = Unifying principles of regeneration I: Epimorphosis versus morphallaxis | journal = Development, Growth & Differentiation | volume = 49 | issue = 2 | pages = 73–8 | date = February 2007 | pmid = 17335428 | doi = 10.1111/j.1440-169X.2007.00919.x | s2cid = 29433846 | doi-access = free }} 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.

During Hydra head regeneration there are coordinated gene expression and chromatin regulation changes.Murad R, Macias-Muñoz A, Wong A, Ma X, Mortazavi A. Coordinated Gene Expression and Chromatin Regulation during Hydra Head Regeneration. Genome Biol Evol. 2021 Dec 1;13(12):evab221. doi: 10.1093/gbe/evab221. PMID 34877597; PMCID: PMC8651858 An enhancer is a short DNA sequence (50–1500 base pairs) that can be bound by transcription factors to increase the transcription of a particular gene. In the enhancer regions that are activated during head regeneration, a set of transcription factor motifs commonly occur that appear to facilitate coordinated gene expression.

Owing to a limited literature on the subject, birds are believed to have very limited regenerative abilities as adults. Some studies{{cite book | title = Asexual Reproduction and Regeneration | vauthors = Vorontsova MA, Liosner LD | veditors = Billet F | translator-first = PM | translator-last1 = Allen | publisher = Pergamon Press | year = 1960 | location = London | pages = 367–371 }} 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.{{cite journal | vauthors = Sidorova VF | title = Liver regeneration in birds | journal = Biulleten' Eksperimental'noi Biologii I Meditsiny | volume = 52 | issue = 6 | pages = 1426–9 | date = July 1962 | pmid = 14039265 | doi = 10.1007/BF00785312 | s2cid = 39410595 }} Birds are also capable of regenerating the hair cells in their cochlea following noise damage or ototoxic drug damage.{{cite journal | vauthors = Cotanche DA, Lee KH, Stone JS, Picard DA | title = Hair cell regeneration in the bird cochlea following noise damage or ototoxic drug damage | journal = Anatomy and Embryology | volume = 189 | issue = 1 | pages = 1–18 | date = January 1994 | pmid = 8192233 | doi = 10.1007/BF00193125 | s2cid = 25619337 }} 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.{{cite journal | vauthors = Coleman CM | title = Chicken embryo as a model for regenerative medicine | journal = Birth Defects Research. Part C, Embryo Today | volume = 84 | issue = 3 | pages = 245–56 | date = September 2008 | pmid = 18773459 | doi = 10.1002/bdrc.20133 }} 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.{{cite journal | vauthors = Özpolat BD, Zapata M, Daniel Frugé J, Coote J, Lee J, Muneoka K, Anderson R | title = Regeneration of the elbow joint in the developing chick embryo recapitulates development | journal = Developmental Biology | volume = 372 | issue = 2 | pages = 229–38 | date = December 2012 | pmid = 23036343 | pmc = 3501998 | doi = 10.1016/j.ydbio.2012.09.020 }}

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.{{cite journal | last = Hosker | first = Anne | name-list-style = vanc | title = Regeneration of Feathers after Thyroid Feeding | date = 1936 | journal = Journal of Experimental Biology | volume = 13 | issue = 3 | pages = 344–351 | doi = 10.1242/jeb.13.3.344 | url = http://jeb.biologists.org/content/13/3/344 | doi-access = free }}

File:Spiny Mice.jpg

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.{{cite journal | vauthors = Kresie L | title = Artificial blood: an update on current red cell and platelet substitutes | journal = Proceedings | volume = 14 | issue = 2 | pages = 158–61 | date = April 2001 | pmid = 16369608 | pmc = 1291332 | doi = 10.1080/08998280.2001.11927754}}{{cite journal | vauthors = Li C, Pearson A, McMahon C | title = Morphogenetic mechanisms in the cyclic regeneration of hair follicles and deer antlers from stem cells | journal = BioMed Research International | volume = 2013 | page = 643601 | date = 2013 | pmid = 24383056 | pmc = 3870647 | doi = 10.1155/2013/643601 | doi-access = free }} 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.{{cite journal | vauthors = Price J, Allen S | title = Exploring the mechanisms regulating regeneration of deer antlers | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 359 | issue = 1445 | pages = 809–22 | date = May 2004 | pmid = 15293809 | pmc = 1693364 | doi = 10.1098/rstb.2004.1471 }} 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.{{cite journal | vauthors = Fernando WA, Leininger E, Simkin J, Li N, Malcom CA, Sathyamoorthi S, Han M, Muneoka K | title = Wound healing and blastema formation in regenerating digit tips of adult mice | journal = Developmental Biology | volume = 350 | issue = 2 | pages = 301–10 | date = February 2011 | pmid = 21145316 | pmc = 3031655 | doi = 10.1016/j.ydbio.2010.11.035 }} 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.{{cite journal | vauthors = Seifert AW, Kiama SG, Seifert MG, Goheen JR, Palmer TM, Maden M | title = Skin shedding and tissue regeneration in African spiny mice (Acomys) | journal = Nature | volume = 489 | issue = 7417 | pages = 561–5 | date = September 2012 | pmid = 23018966 | pmc = 3480082 | doi = 10.1038/nature11499 | bibcode = 2012Natur.489..561S }} In addition to these two species, subsequent studies demonstrated that Acomys cahirinus could regenerate skin and excised tissue in the ear pinna.{{cite journal | vauthors = Gawriluk TR, Simkin J, Thompson KL, Biswas SK, Clare-Salzler Z, Kimani JM, Kiama SG, Smith JJ, Ezenwa VO, Seifert AW | title = Comparative analysis of ear-hole closure identifies epimorphic regeneration as a discrete trait in mammals | journal = Nature Communications | volume = 7 | page = 11164 | date = April 2016 | pmid = 27109826 | pmc = 4848467 | doi = 10.1038/ncomms11164 | bibcode = 2016NatCo...711164G }}{{cite journal | vauthors = Matias Santos D, Rita AM, Casanellas I, Brito Ova A, Araújo IM, Power D, Tiscornia G | title = Ear wound regeneration in the African spiny mouse Acomys cahirinus | journal = Regeneration | volume = 3 | issue = 1 | pages = 52–61 | date = February 2016 | pmid = 27499879 | pmc = 4857749 | doi = 10.1002/reg2.50 }}

Despite these examples, it is generally accepted that adult mammals have limited regenerative capacity compared to most vertebrate embryos/larvae, adult salamanders and fish.{{cite web | first = Kevin | last = Xu | name-list-style = vanc | title = Humans' Ability To Regenerate Damaged Organs Is At Our Fingertips | url = http://www.businessinsider.com/how-regeneration-works-2013-7 | work = Business Insider | date = July 2013 }} But the regeneration therapy approach of Robert O. Becker, using electrical stimulation, has shown promising results for rats{{cite journal | vauthors = Becker RO | title = Stimulation of partial limb regeneration in rats | journal = Nature | volume = 235 | issue = 5333 | pages = 109–11 | date = January 1972 | pmid = 4550399 | doi = 10.1038/235109a0 | bibcode = 1972Natur.235..109B | s2cid = 4209650 }} and mammals in general.{{cite journal | vauthors = Becker RO, Spadaro JA | title = Electrical stimulation of partial limb regeneration in mammals | journal = Bulletin of the New York Academy of Medicine | volume = 48 | issue = 4 | pages = 627–41 | date = May 1972 | pmid = 4503923 | pmc = 1806700 }}

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.{{cite journal | vauthors = Masinde G, Li X, Baylink DJ, Nguyen B, Mohan S | title = Isolation of wound healing/regeneration genes using restrictive fragment differential display-PCR in MRL/MPJ and C57BL/6 mice | journal = Biochemical and Biophysical Research Communications | volume = 330 | issue = 1 | pages = 117–22 | date = April 2005 | pmid = 15781240 | doi = 10.1016/j.bbrc.2005.02.143 }}{{cite journal | vauthors = Hayashi ML, Rao BS, Seo JS, Choi HS, Dolan BM, Choi SY, Chattarji S, Tonegawa S | title = Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 27 | pages = 11489–94 | date = July 2007 | pmid = 17592139 | pmc = 1899186 | doi = 10.1073/pnas.0705003104 | bibcode = 2007PNAS..10411489H | doi-access = free }} 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.{{cite journal | vauthors = Bedelbaeva K, Snyder A, Gourevitch D, Clark L, Zhang XM, Leferovich J, Cheverud JM, Lieberman P, Heber-Katz E | title = Lack of p21 expression links cell cycle control and appendage regeneration in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 13 | pages = 5845–50 | date = March 2010 | pmid = 20231440 | pmc = 2851923 | doi = 10.1073/pnas.1000830107 | bibcode = 2010PNAS..107.5845B | doi-access = free }}

• {{cite web |date=March 15, 2010 |title=1 gene lost = 1 limb regained? Scientists demonstrate mammalian regeneration through single gene deletion |website=Medical Xpress |url=https://medicalxpress.com/news/2010-03-gene-lost-limb-regained-scientists.html}}[http://www.popsci.com/science/article/2010-03/humans-could-regenerate-tissue-newts-switchin-single-gene Humans Could Regenerate Tissue Like Newts By Switching Off a Single 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.{{cite journal | vauthors = Abdullah I, Lepore JJ, Epstein JA, Parmacek MS, Gruber PJ | title = MRL mice fail to heal the heart in response to ischemia-reperfusion injury | journal = Wound Repair and Regeneration | volume = 13 | issue = 2 | pages = 205–8 | date = March–April 2005 | pmid = 15828946 | doi = 10.1111/j.1067-1927.2005.130212.x | s2cid = 7360046 }} However, recent studies provide evidence that this may not always be the case, and that MRL mice can regenerate after heart damage.{{cite web|url=http://www.eurekalert.org/pub_releases/2001-08/wi-rit080201.php |title=Regeneration in the mammalian heart demonstrated by Wistar researchers | EurekAlert! Science News |publisher=Eurekalert.org |access-date=2019-03-16}}

{{Main|Regeneration in humans}}{{See also|Tissue engineering}}

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.{{cite web | last1 = Min | first1 = Su | last2 = Wang | first2 = Song W. | last3 = Orr | first3 = William | name-list-style = vanc | title = Graphic general pathology: 2.2 complete regeneration | work = Pathology | publisher = pathol.med.stu.edu.cn | year = 2006 | quote = 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. | url = http://pathol.med.stu.edu.cn/pathol/listEngContent2.aspx?ContentID=492 | archive-url = https://web.archive.org/web/20121207231322/http://pathol.med.stu.edu.cn/pathol/listEngContent2.aspx?ContentID=492 | archive-date = 2012-12-07 | access-date = 2013-11-10 }} Human organs that have been regenerated include the bladder, vagina and the penis.{{cite web | last =Mohammadi | first = Dara | name-list-style = vanc | title = Bioengineered organs: The story so far... | work = The Guardian | date = 4 October 2014 | url = https://www.theguardian.com/education/2014/oct/04/penis-transplants-anthony-atala-interview | access-date = 9 March 2015 }}

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.{{cite book | title = Principles of Regenerative Biology | url = https://archive.org/details/principlesregene00carl | url-access = limited | vauthors = Carlson BM | publisher = Academic Press | year = 2007 | pages = [https://archive.org/details/principlesregene00carl/page/n45 25]–26 | isbn = 978-0-12-369439-3 }} 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.{{cite journal | vauthors = Ferenczy A, Bertrand G, Gelfand MM | title = Proliferation kinetics of human endometrium during the normal menstrual cycle | journal = American Journal of Obstetrics and Gynecology | volume = 133 | issue = 8 | pages = 859–67 | date = April 1979 | pmid = 434029 | doi = 10.1016/0002-9378(79)90302-8 }}

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.{{cite journal | vauthors = Michalopoulos GK, DeFrances MC | title = Liver regeneration | journal = Science | volume = 276 | issue = 5309 | pages = 60–6 | date = April 1997 | pmid = 9082986 | doi = 10.1126/science.276.5309.60 | s2cid = 2756510 }}{{cite journal | vauthors = Taub R | title = Liver regeneration: from myth to mechanism | journal = Nature Reviews Molecular Cell Biology | volume = 5 | issue = 10 | pages = 836–47 | date = October 2004 | pmid = 15459664 | doi = 10.1038/nrm1489 | s2cid = 30647609 }} For example, the original mass of the liver is re-established in direct proportion to the amount of liver removed following partial hepatectomy,{{cite journal | vauthors = Kawasaki S, Makuuchi M, Ishizone S, Matsunami H, Terada M, Kawarazaki H | title = Liver regeneration in recipients and donors after transplantation | journal = Lancet | volume = 339 | issue = 8793 | pages = 580–1 | date = March 1992 | pmid = 1347095 | doi = 10.1016/0140-6736(92)90867-3 | s2cid = 34148354 }} 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.{{cite journal | vauthors = Vlahopoulos SA | title = Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode | journal = Cancer Biology & Medicine | volume = 14 | issue = 3 | pages = 254–270 | date = August 2017 | pmid = 28884042 | pmc = 5570602 | doi = 10.20892/j.issn.2095-3941.2017.0029 }}

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.{{cite journal | vauthors = 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 | title = Dynamics of hippocampal neurogenesis in adult humans | journal = Cell | volume = 153 | issue = 6 | pages = 1219–1227 | date = June 2013 | pmid = 23746839 | pmc = 4394608 | doi = 10.1016/j.cell.2013.05.002 }} Cardiac myocyte renewal has been found to occur in normal adult humans,{{cite journal | vauthors = 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 | title = Evidence for cardiomyocyte renewal in humans | journal = Science | volume = 324 | issue = 5923 | pages = 98–102 | date = April 2009 | pmid = 19342590 | pmc = 2991140 | doi = 10.1126/science.1164680 | bibcode = 2009Sci...324...98B }} and at a higher rate in adults following acute heart injury such as infarction.{{cite journal | vauthors = Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, Anversa P | title = Evidence that human cardiac myocytes divide after myocardial infarction | journal = The New England Journal of Medicine | volume = 344 | issue = 23 | pages = 1750–7 | date = June 2001 | pmid = 11396441 | doi = 10.1056/NEJM200106073442303 | doi-access =free }}{{Expression of Concern|doi=10.1056/NEJMe1813801|pmid=30332558}} 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 phalanx amputation distal to the nail bed (especially in children){{cite journal | vauthors = McKim LH | title = Regeneration of the distal phalanx | journal = Canadian Medical Association Journal | volume = 26 | issue = 5 | pages = 549–50 | date = May 1932 | pmid = 20318716 | pmc = 402335 }}{{cite journal | vauthors = Muneoka K, Allan CH, Yang X, Lee J, Han M | title = Mammalian regeneration and regenerative medicine | journal = Birth Defects Research. Part C, Embryo Today | volume = 84 | issue = 4 | pages = 265–80 | date = December 2008 | pmid = 19067422 | doi = 10.1002/bdrc.20137 }} and rib regeneration, which occurs following osteotomy for scoliosis treatment (though usually regeneration is only partial and may take up to one year).{{cite journal | vauthors = Philip SJ, Kumar RJ, Menon KV | title = Morphological study of rib regeneration following costectomy in adolescent idiopathic scoliosis | journal = European Spine Journal | volume = 14 | issue = 8 | pages = 772–6 | date = October 2005 | pmid = 16047208 | pmc = 3489251 | doi = 10.1007/s00586-005-0949-8 }}

Yet another example of regeneration in humans is vas deferens regeneration, which occurs after a vasectomy and which results in vasectomy failure.{{cite web |author=Korin Miller |date=September 11, 2017 |url=https://www.self.com/story/what-happens-when-a-vasectomy-fails |title=Here's What Happens When a Vasectomy Fails |publisher=SELF |access-date=2019-03-16}}

The ability and degree of regeneration in reptiles differs among the various species (see {{cite journal | vauthors = Alibardi A, Meyer-Rochow VB | title = Regeneration in reptiles generally and the New Zealand tuatara in particular as a model to analyze organ regrowth in amniotes: A Review | journal = Journal of Developmental Biology | date = 2021 | volume = 9 | issue = 3 | page = 36 | doi = 10.3390/jdb9030036 | pmid = 34564085 | pmc = 8482124 | doi-access = free }}), but the most notable and well-studied occurrence is tail-regeneration in lizards.{{Cite book|last = Alibardi|first = Lorenzo | title=Morphological and Cellular Aspects of Tail and Limb Regeneration in Lizards | series=Advances in Anatomy, Embryology and Cell Biology | name-list-style = vanc |location = Heidelberg | publisher = Springer|year = 2010|isbn = 978-3-642-03732-0|pages = iii, v-x, 1–109|chapter = Regeneration in Reptiles and Its Position Among Vertebrates|volume = 207|doi = 10.1007/978-3-642-03733-7_1|pmid = 20334040}}{{cite journal | vauthors = McLean KE, Vickaryous MK | title = A novel amniote model of epimorphic regeneration: the leopard gecko, Eublepharis macularius | journal = BMC Developmental Biology | volume = 11 | issue = 1 | page = 50 | date = August 2011 | pmid = 21846350 | pmc = 3180301 | doi = 10.1186/1471-213x-11-50 | doi-access = free }}{{Cite book|title = Biology of the Reptilia|last1 = Bellairs|first1 = A.|publisher = John Wiley and Sons|year = 1985|location = New York|pages = 301–410|last2 = Bryant|first2 = S.|volume = 15|editor-last = Gans|editor-first2 = F.|editor-last2 = Billet|editor-first = Carl | name-list-style = vanc |chapter = Autonomy and Regeneration in Reptiles}} In addition to lizards, regeneration has been observed in the tails and maxillary bone of crocodiles and adult neurogenesis has also been noted.{{cite journal |title = Maxillary Regeneration in a Marsh Crocodile, Crocodylus palustris|last = Brazaitis|first = Peter | name-list-style = vanc |date = July 31, 1981|journal = Journal of Herpetology|doi = 10.2307/1563441 |issue = 3|volume = 15|pages = 360–362|jstor = 1563441}}{{cite journal | vauthors = Font E, Desfilis E, Pérez-Cañellas MM, García-Verdugo JM | title = Neurogenesis and neuronal regeneration in the adult reptilian brain | journal = Brain, Behavior and Evolution | volume = 58 | issue = 5 | pages = 276–95 | date = 2001 | pmid = 11978946| doi = 10.1159/000057570 | s2cid = 1079753 }} Tail regeneration has never been observed in snakes, but see. Lizards possess the highest regenerative capacity as a group.{{cite web | first = Matt | last = Vickaryous | name-list-style = vanc | year = 2014| url = http://www.vickaryouslab.com | title = Vickaryous Lab: Regeneration - Evolution - Development | publisher = Department of Biomedical Sciences, University of Guelph }} 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.

It has been estimated that the average shark loses about 30,000 to 40,000 teeth in a lifetime. 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.

Rhodopsin regeneration has been studied in skates and rays. After complete photo-bleaching, rhodopsin can completely regenerate within 2 hours in the retina.{{cite journal |vauthors=Sun Y, Ripps H |date=November 1992 |title=Rhodopsin regeneration in the normal and in the detached/replaced retina of the skate |journal=Experimental Eye Research |volume=55 |issue=5 |pages=679–89 |doi=10.1016/0014-4835(92)90173-p |pmid=1478278}}

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.{{cite journal |vauthors=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 |date=2013 |title=Study of microRNAs related to the liver regeneration of the whitespotted bamboo shark, Chiloscyllium plagiosum |journal=BioMed Research International |volume=2013 |page=795676 |doi=10.1155/2013/795676 |pmc=3789328 |pmid=24151623 |doi-access=free}}

Some sharks can regenerate scales and even skin following damage. Within two weeks of skin wounding, 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.{{Cite journal |last=Reif |first=Wolf-Ernst |name-list-style=vanc |date=June 1978 |title=Wound Healing in Sharks |journal=Zoomorphology |volume=90 |issue=2 |pages=101–111 |doi=10.1007/bf02568678 |s2cid=29300907}}

• Autotomy
• Cloning
• Regenerative medicine
• Neuroregeneration
• Organ transplantation
• Epimorphosis
• Morphallaxis
• Polyphyodont

{{Reflist|32em}}

{{Refbegin|32em}}

• {{cite journal | vauthors = Tanaka EM | title = Cell differentiation and cell fate during urodele tail and limb regeneration | journal = Current Opinion in Genetics & Development | volume = 13 | issue = 5 | pages = 497–501 | date = October 2003 | pmid = 14550415 | doi = 10.1016/j.gde.2003.08.003 }}
• {{cite journal | vauthors = Holland ND | title = Vicenzo Colucci's 1886 memoir, Intorno alla rigenerazione degli arti e della coda nei tritoni, annotated and translated into English as: Concerning regeneration of the limbs and tail in salamanders | journal = The European Zoological Journal | volume = 88 | pages = 837–890 | year= 2021| doi = 10.1080/24750263.2021.1943549| s2cid = 238904520 | doi-access = free }}
• {{cite journal | vauthors = Nye HL, Cameron JA, Chernoff EA, Stocum DL | title = Regeneration of the urodele limb: a review | journal = Developmental Dynamics | volume = 226 | issue = 2 | pages = 280–94 | date = February 2003 | pmid = 12557206 | doi = 10.1002/dvdy.10236 | s2cid = 28442979 | doi-access = free }}
• {{cite journal | vauthors = Yu H, Mohan S, Masinde GL, Baylink DJ | title = Mapping the dominant wound healing and soft tissue regeneration QTL in MRL x CAST | journal = Mammalian Genome | volume = 16 | issue = 12 | pages = 918–24 | date = December 2005 | pmid = 16341671 | doi = 10.1007/s00335-005-0077-0 | s2cid = 24505367 }}
• {{cite journal | vauthors = Gardiner DM, Blumberg B, Komine Y, Bryant SV | title = Regulation of HoxA expression in developing and regenerating axolotl limbs | journal = Development | volume = 121 | issue = 6 | pages = 1731–41 | date = June 1995 | doi = 10.1242/dev.121.6.1731 | pmid = 7600989 | url = http://www.escholarship.org/uc/item/3b97d88q }}
• {{cite journal | vauthors = Torok MA, Gardiner DM, Shubin NH, Bryant SV | title = Expression of HoxD genes in developing and regenerating axolotl limbs | journal = Developmental Biology | volume = 200 | issue = 2 | pages = 225–33 | date = August 1998 | pmid = 9705229 | doi = 10.1006/dbio.1998.8956 | doi-access = free }}
• {{cite journal | vauthors = 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 | title = From biomedicine to natural history research: EST resources for ambystomatid salamanders | journal = BMC Genomics | volume = 5 | issue = 1 | page = 54 | date = August 2004 | pmid = 15310388 | pmc = 509418 | doi = 10.1186/1471-2164-5-54 | doi-access = free }}
• {{cite news | title=Medicine's Cutting Edge: Re-Growing Organs | url = https://www.cbsnews.com/news/medicines-cutting-edge-re-growing-organs/ | work=Sunday Morning | publisher = CBS News | last = Andrews | first = Wyatt | date = March 23, 2008

| url-status=live |archive-url=https://web.archive.org/web/20080324220616/http://www.cbsnews.com/stories/2008/03/22/sunday/main3960219.shtml |archive-date=2008-03-24}}

{{Refend}}

• Kevin Strange and Viravuth Yin, "A Shot at Regeneration: A once abandoned drug compound shows an ability to rebuild organs damaged by illness and injury", Scientific American, vol. 320, no. 4 (April 2019), pp. 56–61.

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{{EB1911 poster|Regeneration of Lost Parts}}

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Category:Healing

Category:Developmental biology

Category:Senescence