[{"command":"settings","settings":{"ajaxPageState":{"theme":"hm_theme","theme_token":"waQwoP_9VJEtl0g9EMHLGFf9UuvAQ1QQMRsHue8VTUM","libraries":"eJwDAAAAAAE"},"ajaxTrustedUrl":{"form_action_p_pvdeGsVG5zNF_XLGPTvYSKCf43t8qZYSwcfZl2uzM":true},"pluralDelimiter":"\u0003","user":{"uid":0,"permissionsHash":"2af85631393b514cbde3779a1f71d92618d53b94b54ea1960d28b2e2d121ff12"}},"merge":true},{"command":"openDialog","selector":"#drupal-modal","settings":null,"data":"\u003Cdiv id=\u0022republish_modal_form\u0022\u003E\u003Cform class=\u0022modal-form-example-modal-form ecl-form\u0022 data-drupal-selector=\u0022modal-form-example-modal-form\u0022 action=\u0022\/en\/article\/modal\/9679\u0022 method=\u0022post\u0022 id=\u0022modal-form-example-modal-form\u0022 accept-charset=\u0022UTF-8\u0022\u003E\u003Cp\u003EHorizon articles can be republished for free under the Creative Commons Attribution 4.0 International (CC BY 4.0) licence.\u003C\/p\u003E\n \u003Cp\u003EYou must give appropriate credit. We ask you to do this by:\u003Cbr \/\u003E\n 1) Using the original journalist\u0027s byline\u003Cbr \/\u003E\n 2) Linking back to our original story\u003Cbr \/\u003E\n 3) Using the following text in the footer: This article was originally published in \u003Ca href=\u0027#\u0027\u003EHorizon, the EU Research and Innovation magazine\u003C\/a\u003E\u003C\/p\u003E\n \u003Cp\u003ESee our full republication guidelines \u003Ca href=\u0027\/horizon-magazine\/republish-our-stories\u0027\u003Ehere\u003C\/a\u003E\u003C\/p\u003E\n \u003Cp\u003EHTML for this article, including the attribution and page view counter, is below:\u003C\/p\u003E\u003Cdiv class=\u0022js-form-item form-item js-form-type-textarea form-item-body-content js-form-item-body-content ecl-form-group ecl-form-group--text-area form-no-label ecl-u-mv-m\u0022\u003E\n \n\u003Cdiv\u003E\n \u003Ctextarea data-drupal-selector=\u0022edit-body-content\u0022 aria-describedby=\u0022edit-body-content--description\u0022 id=\u0022edit-body-content\u0022 name=\u0022body_content\u0022 rows=\u00225\u0022 cols=\u002260\u0022 class=\u0022form-textarea ecl-text-area\u0022\u003E\u003Ch2\u003E Limb-regenerating fire-god salamander central to wound repair quest\u003C\/h2\u003E\u003Cp\u003ESalamanders are remarkable creatures. If one of these amphibians loses a finger, it grows back. Furthermore, if you chop away a piece of heart or spinal cord, it will regenerate. Perhaps most impressively, they can even regrow a leg bitten off by a hungry predator.\u003C\/p\u003E\u003Cp\u003EOne of the most famous salamander species is the axolotl (Ambystoma mexicanum), which is found in lakes near Mexico City.\u003C\/p\u003E\u003Cp\u003EThe axolotl is a veritable Peter Pan of salamanders. Even the 30-centimetre-long reproductive adult retains features of its youthful phase throughout its lifecycle.\u003C\/p\u003E\u003Cp\u003EThe prominent gills protruding from the back of its head are retained from the axolotl\u0027s larval phase. The fact that it never leaves the water throughout its life is unusual for an amphibian.\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EFire god\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003EAxolotls were named after the Aztec god of fire Xolotl who, legend has it, disguised himself as a salamander to avoid being sacrificed. Today, scientists study axolotls in their laboratories because of their amazing ability to regrow one or even two limbs.\u003C\/p\u003E\u003Cp\u003E\u2018I\u2019m still fascinated by how the limbs regenerate,\u2019 said Professor Elly Tanaka at the Research Institute of Molecular Pathology in Vienna, Austria, who has studied salamanders for almost two decades.\u003C\/p\u003E\u003Cp\u003EHer lab focuses on the distinctive axolotl species but \u2018All salamanders people have studied seem to regenerate limbs,\u0027 she remarks.\u003C\/p\u003E\u003Cp\u003EAs part of the EU-funded \u003Ca href=\u0022https:\/\/cordis.europa.eu\/project\/id\/742046\u0022\u003ERegGeneMems project\u003C\/a\u003E, Prof Tanaka is trying to unravel the mystery behind how molecules command cells inside the injured axolotl to develop and move, thereby restoring an entire limb in the right proportion and size.\u003C\/p\u003E\u003Cp\u003EThis regeneration is possible as far as the shoulder, and it happens as if the animal was first growing a limb.\u003C\/p\u003E\u003Cp\u003EWhile it remains within the realms of science-fiction for a person ever to regrow an arm or a leg, researchers believe that the salamanders can offer insights into how patient injuries might be better treated.\u003C\/p\u003E\u003Cp\u003E\u2018When they lose a limb, or even two limbs, they\u2019re still pretty mobile because they can swim around using their tail,\u2019 said Prof Tanaka.\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003ECellular kit\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003E\u2018The lesson from the salamanders is that you use very much the same molecular machinery that you do during the development of the limb,\u2019 said Prof Tanaka. With lessons from the axolotl, we could therefore boost our own injury-repair kit.\u003C\/p\u003E\u003Cp\u003EOnce an axolotl limb is lost, a blood clot forms at the site of the wound. Skin cells move to cover the wound within a day. Then the tissues underneath start rearranging, first forming a jumbled mass of cells - a blastema - that seems to lack any organisation. \u0026nbsp;\u003C\/p\u003E\u003Cp\u003E\u003Cblockquote class=\u0022tw-text-center tw-text-blue tw-font-bold tw-text-2xl lg:tw-w-1\/2 tw-border-2 tw-border-blue tw-p-12 tw-my-8 lg:tw-m-12 lg:tw--ml-16 tw-float-left\u0022\u003E\n \u003Cspan class=\u0022tw-text-5xl tw-rotate-180\u0022\u003E\u201c\u003C\/span\u003E\n \u003Cp class=\u0022tw-font-serif tw-italic\u0022\u003EAll salamanders people have studied seem to regenerate limbs.\u003C\/p\u003E\n \u003Cfooter\u003E\n \u003Ccite class=\u0022tw-not-italic tw-font-normal tw-text-sm tw-text-black\u0022\u003EProf Elly Tanaka, ReGeneMems\u003C\/cite\u003E\n \u003C\/footer\u003E\n\u003C\/blockquote\u003E\n\u003C\/p\u003E\u003Cp\u003EA blastema is a mass of undifferentiated cells that has the capacity to turn into an organ or appendage. It is particularly important in the regeneration of severed limbs.\u003C\/p\u003E\u003Cp\u003EIn human wounds, scar tissue is formed by glue-like cells called fibroblasts. In salamanders, something amazing happens as, within weeks, these cells take a step back in time to become less specialized.\u003C\/p\u003E\u003Cp\u003EThey regain enough flexibility to become bone, ligament, tendon, or cartilage. Then, they shoot each other signals that direct the reconstruction of the missing body part from the stump, growing an exact replicate.\u003C\/p\u003E\u003Cp\u003EProf Tanaka recently discovered how some crucial signals help with the arrangement of cells and tissues from what looks like a confused jumble.\u003C\/p\u003E\u003Cp\u003EShe discovered that cells in the regenerating tissue that come from the thumb side of the limb start to produce different signals than cells from the pinky-finger side.\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003ESonic Hedgehog\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003E\u2018The thumb side produces FGF-8 (fibroblast growth factor), and this tells the pinky-side cells that they need to produce Sonic Hedgehog,\u2019 said Prof Tanaka.\u003C\/p\u003E\u003Cp\u003ENamed in honour of the famous Sonic the Hedgehog videogame character, the Sonic Hedgehog signalling molecule (SHH) is crucial to embryonic development in animals and humans.\u003C\/p\u003E\u003Cp\u003EAnother signal molecule, also found in people, is FGF-8, which also has a role in tissue repair and development.\u003C\/p\u003E\u003Cp\u003E\u003Cfigure role=\u0022group\u0022\u003E\n\u003Cimg alt=\u0022The axolotyl can regenerate severed limbs. \u00a9 Amandasofiarana, CC BY-SA 4.0, via Wikimedia Commons\u0022 data-entity-type=\u0022file\u0022 data-entity-uuid=\u00228e3ca281-f57f-4e94-98d8-aaa9f2c84235\u0022 src=\u0022\/sites\/default\/files\/hm\/IMCEUpload\/BODY%20Axolotl_ambystoma_mexicanum_anfibio_ASAG.jpg\u0022\u003E\n\u003Cfigcaption class=\u0022tw-italic tw-mb-4\u0022\u003EThe axolotyl can regenerate severed limbs. \u00a9 Amandasofiarana, CC BY-SA 4.0, via Wikimedia Commons\u003C\/figcaption\u003E\n\u003C\/figure\u003E\n\u003C\/p\u003E\u003Cp\u003ETogether, FGF-8 and SHH stoke pro-growth conditions inside the damaged limb and help direct the jumble of cells in the blastema.\u003C\/p\u003E\u003Cp\u003E\u2018You need cells from the pinky and thumb side of the limb to come into this blastema, and so you have all the cell types that you need to rebuild,\u2019 said Prof Tanaka.\u003C\/p\u003E\u003Cp\u003EAnother scientist intrigued by axolotls is cell biologist Dr Sandra Edwards at TU Dresden. She became interested in salamanders after attending a research course in the US during her PhD in Chile, redirecting her career. \u0026nbsp;\u003C\/p\u003E\u003Cp\u003EShe applied to join the lab of Tatiana Sandoval-Guzm\u00e1n, an eminent researcher of axolotl limb repair at the Centre for Regenerative Therapies Dresden (CRTD).\u003C\/p\u003E\u003Cp\u003E\u2018The more I heard about salamanders, the more I became fascinated,\u2019 recalled Dr Edwards, who hopes her research can one day go to help patients.\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003ETissue tension\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003EIn the\u0026nbsp;\u003Ca href=\u0022https:\/\/cordis.europa.eu\/project\/id\/101022810\u0022\u003EProDistReg project\u003C\/a\u003E, the \u003Ca href=\u0022https:\/\/marie-sklodowska-curie-actions.ec.europa.eu\/\u0022\u003EMarie Sk\u0142odowska-Curie Actions (MSCA)\u003C\/a\u003E fellow Dr Edwards, studies how differences in tension within tissues may influence the repair and help the animal turn what seems like cellular chaos into a perfectly functioning limb.\u003C\/p\u003E\u003Cp\u003E\u003Cblockquote class=\u0022tw-text-center tw-text-blue tw-font-bold tw-text-2xl lg:tw-w-1\/2 tw-border-2 tw-border-blue tw-p-12 tw-my-8 lg:tw-m-12 lg:tw--ml-16 tw-float-left\u0022\u003E\n \u003Cspan class=\u0022tw-text-5xl tw-rotate-180\u0022\u003E\u201c\u003C\/span\u003E\n \u003Cp class=\u0022tw-font-serif tw-italic\u0022\u003EThe more I heard about salamanders, the more I became fascinated.\r\n\u003C\/p\u003E\n \u003Cfooter\u003E\n \u003Ccite class=\u0022tw-not-italic tw-font-normal tw-text-sm tw-text-black\u0022\u003EDr Sandra Edwards, ProDistReg\u003C\/cite\u003E\n \u003C\/footer\u003E\n\u003C\/blockquote\u003E\n\u003C\/p\u003E\u003Cp\u003EShe became intrigued with the fact that limb regrowth takes a similar amount of time, regardless of the amount of tissue being replaced. This means limbs must grow faster when more tissue is removed.\u003C\/p\u003E\u003Cp\u003E\u2018My hypothesis is that tension or stiffness is higher in tissues that grow slower,\u2019 she said.\u003C\/p\u003E\u003Cp\u003EIt may seem surprising, but the mechanics and rigidity of tissues can influence their development and regeneration as well as pathologies like cancer.\u003C\/p\u003E\u003Cp\u003EThere is a web-like network called the cytoskeleton inside cells. This can sense external pressures when compressed, which opens entry points (akin to postal boxes) to the nucleus of a cell, allowing molecular messages to flow in and turn genes on and off.\u003C\/p\u003E\u003Cp\u003E\u0027In our system, we have observed that during limb generation in the axolotl, tissues that are closer to the body are softer and grows faster than tissues that are further away from the body on the end of a limb, for example, which are stiffer.\u0027\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003ECell matrix\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003EKnowledge about tissue stiffness could help injured patients. While conceivably such patients might be treated with stem cells delivered in a matrix, the pressures within the patient\u2019s tissues may prove important.\u003C\/p\u003E\u003Cp\u003E\u2018It may be that the tissues and their cells on different parts of the body behave differently, even within the same structure such as the arm, such as upper and lower arm, said Dr Edwards. Therefore, in regenerative medicine, where cell-containing matrixes are transplanted into large wounds, such scaffolds may need to be different, depending on where in the body they will be placed.\u003C\/p\u003E\u003Cp\u003EThough Prof Tanaka spends most days studying the molecular mechanics of axolotl repair, she too foresees future benefits to injured patients. But salamanders and mammals develop differently.\u003C\/p\u003E\u003Cp\u003EIn mammals, like ourselves, when we first develop an arm, this happens at a tiny scale in an embryo. The salamander is different. It seems to contain a bud capable of developing into a large adult arm.\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EStem cells\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003E\u2018We are not going to be able to ask a human cell to do this, because it\u2019s wired to work at tiny scales,\u2019 said Prof Tanaka. \u2018But we might be able to produce a group of human stem cells that regenerate like an axolotl.\u2019\u003C\/p\u003E\u003Cp\u003EThis could be extremely beneficial, for example, to people who suffer extensive burn wounds. Repair of this skin currently does not give a person sweat glands, hair follicles and other cell types, but lessons from the salamander could make this possible.\u003C\/p\u003E\u003Cp\u003E\u2018Resetting these fibroblasts \u2013 which the axolotl does \u2013 could be quite relevant to better healing in very large wounds, such as from burns,\u2019 Prof Tanaka said.\u003C\/p\u003E\u003Cp\u003E\u003Cem\u003EResearch in this article was funded via the EU\u2019s European Research Council and the Marie Sk\u0142odowska-Curie Actions (MSCA).\u0026nbsp;If you liked this article, please consider sharing it on social media.\u003C\/em\u003E\u003C\/p\u003E\u003C\/textarea\u003E\n\u003C\/div\u003E\n\n \u003Cdiv id=\u0022edit-body-content--description\u0022 class=\u0022ecl-help-block description\u0022\u003E\n Please copy the above code and embed it onto your website to republish.\n \u003C\/div\u003E\n \u003C\/div\u003E\n\u003Cinput autocomplete=\u0022off\u0022 data-drupal-selector=\u0022form-d4wjnsdehefmuxqvcpvb709ywzkeqd1jbmiocj5ptq\u0022 type=\u0022hidden\u0022 name=\u0022form_build_id\u0022 value=\u0022form--D4wJnsdEHeFmUXQVcpVb709YWzKeqD1jBmIocJ5PtQ\u0022 \/\u003E\n\u003Cinput data-drupal-selector=\u0022edit-modal-form-example-modal-form\u0022 type=\u0022hidden\u0022 name=\u0022form_id\u0022 value=\u0022modal_form_example_modal_form\u0022 \/\u003E\n\u003C\/form\u003E\n\u003C\/div\u003E","dialogOptions":{"width":"800","modal":true,"title":"Republish this content"}}]