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Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs

Absence of a specialized wound epidermis is hypothesized to block limb regeneration in higher vertebrates. However, the factors preventing its formation in regeneration-incompetent animals are poorly understood. To characterize the endogenous molecular and cellular regulators of specialized wound ep...

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Autores principales: Aztekin, Can, Hiscock, Tom W., Gurdon, John, Jullien, Jerome, Marioni, John, Simons, Benjamin David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217717/
https://www.ncbi.nlm.nih.gov/pubmed/34105722
http://dx.doi.org/10.1242/dev.199158
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author Aztekin, Can
Hiscock, Tom W.
Gurdon, John
Jullien, Jerome
Marioni, John
Simons, Benjamin David
author_facet Aztekin, Can
Hiscock, Tom W.
Gurdon, John
Jullien, Jerome
Marioni, John
Simons, Benjamin David
author_sort Aztekin, Can
collection PubMed
description Absence of a specialized wound epidermis is hypothesized to block limb regeneration in higher vertebrates. However, the factors preventing its formation in regeneration-incompetent animals are poorly understood. To characterize the endogenous molecular and cellular regulators of specialized wound epidermis formation in Xenopus laevis tadpoles, and the loss of their regeneration competency during development, we used single-cell transcriptomics and ex vivo regenerating limb cultures. Transcriptomic analysis revealed that the specialized wound epidermis is not a novel cell state, but a re-deployment of the apical-ectodermal-ridge (AER) programme underlying limb development. Enrichment of secreted inhibitory factors, including Noggin, a morphogen expressed in developing cartilage/bone progenitor cells, are identified as key inhibitors of AER cell formation in regeneration-incompetent tadpoles. These factors can be overridden by Fgf10, which operates upstream of Noggin and blocks chondrogenesis. These results indicate that manipulation of the extracellular environment and/or chondrogenesis may provide a strategy to restore regeneration potential in higher vertebrates.
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spelling pubmed-82177172021-07-08 Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs Aztekin, Can Hiscock, Tom W. Gurdon, John Jullien, Jerome Marioni, John Simons, Benjamin David Development Stem Cells and Regeneration Absence of a specialized wound epidermis is hypothesized to block limb regeneration in higher vertebrates. However, the factors preventing its formation in regeneration-incompetent animals are poorly understood. To characterize the endogenous molecular and cellular regulators of specialized wound epidermis formation in Xenopus laevis tadpoles, and the loss of their regeneration competency during development, we used single-cell transcriptomics and ex vivo regenerating limb cultures. Transcriptomic analysis revealed that the specialized wound epidermis is not a novel cell state, but a re-deployment of the apical-ectodermal-ridge (AER) programme underlying limb development. Enrichment of secreted inhibitory factors, including Noggin, a morphogen expressed in developing cartilage/bone progenitor cells, are identified as key inhibitors of AER cell formation in regeneration-incompetent tadpoles. These factors can be overridden by Fgf10, which operates upstream of Noggin and blocks chondrogenesis. These results indicate that manipulation of the extracellular environment and/or chondrogenesis may provide a strategy to restore regeneration potential in higher vertebrates. The Company of Biologists Ltd 2021-06-09 /pmc/articles/PMC8217717/ /pubmed/34105722 http://dx.doi.org/10.1242/dev.199158 Text en © 2021. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Stem Cells and Regeneration
Aztekin, Can
Hiscock, Tom W.
Gurdon, John
Jullien, Jerome
Marioni, John
Simons, Benjamin David
Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs
title Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs
title_full Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs
title_fullStr Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs
title_full_unstemmed Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs
title_short Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs
title_sort secreted inhibitors drive the loss of regeneration competence in xenopus limbs
topic Stem Cells and Regeneration
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217717/
https://www.ncbi.nlm.nih.gov/pubmed/34105722
http://dx.doi.org/10.1242/dev.199158
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