Species-specific oxygen sensing governs the initiation of vertebrate limb regeneration
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE314013 | GEO | 2026/05/04
REPOSITORIES: GEO
Similar Datasets
Project description:Why mammals cannot regenerate limbs, unlike amphibians, presents a longstanding puzzle in biology. We show that exposing ex vivo amputated embryonic mouse limbs to subatmospheric oxygen environment, or stabilizing oxygen-sensitive HIF1A enables not only rapid wound healing, but alters cellular mechanics, and reshapes the histone landscape to prime regenerative fates. Conversely, regenerative Xenopus tadpole limbs display low oxygen-sensing capacity, robust wound healing, a regenerative histone landscape, and glycolytic programs even under high oxygen. This reduced oxygen-sensing capacity, in stark contrast to mammals, associates with decreased HIF1A-regulating gene expressions. Our findings thus uncover species-specific oxygen sensing as a unifying mechanism for limb regeneration initiation across vertebrates, reveal how aquatic subatmospheric habitats may enhance regenerative capabilities, and identify targetable barriers to unlock latent limb regenerative programs in adult mammals.
2026-04-09 | GSE292212 | GEO
Project description:Why mammals cannot regenerate limbs, unlike amphibians, presents a longstanding puzzle in biology. We show that exposing ex vivo amputated embryonic mouse limbs to subatmospheric oxygen environment, or stabilizing oxygen-sensitive HIF1A enables not only rapid wound healing, but alters cellular mechanics, and reshapes the histone landscape to prime regenerative fates. Conversely, regenerative Xenopus tadpole limbs display low oxygen-sensing capacity, robust wound healing, a regenerative histone landscape, and glycolytic programs even under high oxygen. This reduced oxygen-sensing capacity, in stark contrast to mammals, associates with decreased HIF1A-regulating gene expressions. Our findings thus uncover species-specific oxygen sensing as a unifying mechanism for limb regeneration initiation across vertebrates, reveal how aquatic subatmospheric habitats may enhance regenerative capabilities, and identify targetable barriers to unlock latent limb regenerative programs in adult mammals.
2026-04-09 | GSE292215 | GEO
Project description:Why mammals cannot regenerate limbs, unlike amphibians, presents a longstanding puzzle in biology. We show that exposing ex vivo amputated embryonic mouse limbs to subatmospheric oxygen environment, or stabilizing oxygen-sensitive HIF1A enables not only rapid wound healing, but alters cellular mechanics, and reshapes the histone landscape to prime regenerative fates. Conversely, regenerative Xenopus tadpole limbs display low oxygen-sensing capacity, robust wound healing, a regenerative histone landscape, and glycolytic programs even under high oxygen. This reduced oxygen-sensing capacity, in stark contrast to mammals, associates with decreased HIF1A-regulating gene expressions. Our findings thus uncover species-specific oxygen sensing as a unifying mechanism for limb regeneration initiation across vertebrates, reveal how aquatic subatmospheric habitats may enhance regenerative capabilities, and identify targetable barriers to unlock latent limb regenerative programs in adult mammals.
2026-04-09 | GSE292734 | GEO
Project description:Identifying the genetic program that induces limb regeneration in salamanders is an important resource for regenerative medicine, which currently lacks tools to promote regeneration of functional body structures. The genetic network underlying limb regeneration has been elusive due to the complexity of the injury response that occurs concomitant to blastema formation. Here we performed parallel expression profile time courses of non-regenerative lateral wounds versus amputated limbs in axolotl. We show that limb regeneration occurs in three distinguishable phases--early wound healing followed by a transition phase leading to establishment of the limb development program. By focusing on the transition phase, we identified 93 strictly regeneration-associated genes involved in oxidative stress response, chromatin modification, epithelial development and limb development. The specific expression of the genes was confirmed by in situ hybridization. Regeneration-specific expression databases are critical resources for understanding how regeneration-relevant phenotypes can be induced from adult cells Regeneration of the axolotl forelimb lower arm was compared with the healing of a deep lateral injury in a high density timecourse (uncut, 3h, 6h, 9h, 12h, 24h, 36h, 52h, 72h, 120h, 168h, 288h and 528h after injury). Three independent biological replicates were performed using separate cluches of animals. Amputated and lateral wound samples were made as matched contralateral samples of four pooled animals per timepoint.
2013-01-01 | E-GEOD-36451 | biostudies-arrayexpress
Project description:Salamander limb regeneration is dependent upon tissue interactions that are local to the amputation site. Communication among limb epidermis, peripheral nerves, and mesenchyme coordinate cell migration, cell proliferation, and tissue patterning to generate a blastema, a mass of progenitor cells that forms missing limb structures. An outstanding question is how molecular cross-talk between these tissues gives rise to the regeneration blastema. To identify genes associated with epidermis-nerve-mesenchymal interactions during limb regeneration, we examined histological and transcriptional changes during the first week following injury in the wound epidermis and subjacent cells between three injury types; 1) a flank wound on the side of the animal that will not regenerate a limb, 2) a denervated limb that will not regenerate a limb, and 3) an innervated limb that will regenerate a limb. Early, histological and transcriptional changes were highly similar between the three injury types, presumably because a common wound-healing program is employed across anatomical locations. However, we identified transcripts that were enriched in the limb compared to the flank and are associated with vertebrate limb development. Many of these genes were activated before blastema outgrowth and in situ hybridization showed that some of these genes were expressed in specific tissue types including the epidermis, peripheral nerve, and mesenchyme. We also identified a relatively small group of transcripts that were more highly expressed in innervated limbs versus denervated limbs. These transcripts encode for proteins that are associated with myelination of peripheral nerves, epidermal maintenance, and cell proliferation, suggesting that denervation affects myelinating Schwann cells, epidermal cell function, and proliferation of mesenchymal cells. Overall, our study identifies limb-specific and nerve-dependent genes that are upstream of regenerative growth, and thus promising candidates for the regulation of blastema formation. We used microarray analysis to determine the gene expression changes that take place during limb regeneration, flank wound healing, and an denervated amputated limb. Epidermal tissue and cells adhered to the epidermis were collected as samples. Two harvested samples was pooled for each animal. Four biological replicates were collected from uninjured epidermis (D0) and at 1, 3, and 7 days post injury.
2012-09-17 | E-GEOD-37198 | biostudies-arrayexpress
Project description:Identifying the genetic program that induces limb regeneration in salamanders is an important resource for regenerative medicine, which currently lacks tools to promote regeneration of functional body structures. The genetic network underlying limb regeneration has been elusive due to the complexity of the injury response that occurs concomitant to blastema formation. Here we performed parallel expression profile time courses of non-regenerative lateral wounds versus amputated limbs in axolotl. We show that limb regeneration occurs in three distinguishable phases--early wound healing followed by a transition phase leading to establishment of the limb development program. By focusing on the transition phase, we identified 93 strictly regeneration-associated genes involved in oxidative stress response, chromatin modification, epithelial development and limb development. The specific expression of the genes was confirmed by in situ hybridization. Regeneration-specific expression databases are critical resources for understanding how regeneration-relevant phenotypes can be induced from adult cells
2013-01-01 | GSE36451 | GEO
Project description:Salamander limb regeneration is dependent upon tissue interactions that are local to the amputation site. Communication among limb epidermis, peripheral nerves, and mesenchyme coordinate cell migration, cell proliferation, and tissue patterning to generate a blastema, a mass of progenitor cells that forms missing limb structures. An outstanding question is how molecular cross-talk between these tissues gives rise to the regeneration blastema. To identify genes associated with epidermis-nerve-mesenchymal interactions during limb regeneration, we examined histological and transcriptional changes during the first week following injury in the wound epidermis and subjacent cells between three injury types; 1) a flank wound on the side of the animal that will not regenerate a limb, 2) a denervated limb that will not regenerate a limb, and 3) an innervated limb that will regenerate a limb. Early, histological and transcriptional changes were highly similar between the three injury types, presumably because a common wound-healing program is employed across anatomical locations. However, we identified transcripts that were enriched in the limb compared to the flank and are associated with vertebrate limb development. Many of these genes were activated before blastema outgrowth and in situ hybridization showed that some of these genes were expressed in specific tissue types including the epidermis, peripheral nerve, and mesenchyme. We also identified a relatively small group of transcripts that were more highly expressed in innervated limbs versus denervated limbs. These transcripts encode for proteins that are associated with myelination of peripheral nerves, epidermal maintenance, and cell proliferation, suggesting that denervation affects myelinating Schwann cells, epidermal cell function, and proliferation of mesenchymal cells. Overall, our study identifies limb-specific and nerve-dependent genes that are upstream of regenerative growth, and thus promising candidates for the regulation of blastema formation.
2012-09-17 | GSE37198 | GEO
Project description:The induction of limb repair depends on signals that initiate regeneration and the successful transmission of those signals in vivo. Here, we characterize the effects of an integrated device-based in vivo delivery of drug compounds in adult Xenopus laevis, which normally regenerate only a cartilaginous spike after limb amputation. A wearable bioreactor containing a silk protein-based hydrogel containing progesterone that was applied to the wound site immediately after hind-limb amputation for 24 hours induced regeneration of flattened paddle-like structures in adult frogs. Molecular assays (ELISA and NGS), Morphometric analysis (soft-tissue patterning), X-ray imaging (bone regrowth), immunofluorescence (cell proliferation, immune response, neuro/vascular tissues), and behavioral data (functional use of regenerates) were used to characterize the differences between the paddle-like structures and the hypomorphic spike observed in untreated animals. Initially, treated animals exhibited an extensive wound epithelium, and increased nerve supply compared to controls. Subsequently, flattened structures with robust bone remodeling were formed, resembling comparable tissues of adult limbs at the early and middle stages of regeneration. The limbs ceased regeneration at the position where the digits usually form. Functional tests revealed that the response to the paddle-like structures was similar to that of uncut limbs. Analysis of the blastema transcriptome identified a number of key genes related to the combined intervention, and also revealed regulated transcripts related to hormonal and neural pathways, representing novel targets for emerging regenerative therapies. Our experiments (1) establish a new model for testing of therapeutic cocktails in vertebrate limb regeneration; (2) identify pro-regenerative activities of progesterone, and (3) provide proof-of-principle of using integrated device-based delivery of small molecule drugs as a viable strategy to induce and maintain a regenerative response.
2019-01-09 | GSE118454 | GEO
Project description:Premetamorphic Xenopus laevis tadpoles limbs develop in response to thyroid hormone by proliferation and subsequent differentiation. We have previously reported that inhibiting the thyroid hormone action using a dominant negative receptor in limbs of developing tadpoles inhibits its growth and the tadpole limb has almost no muscle. The goal of this experiment is to study the role of thyroid hormone in the maintenance of limb muscle using transgenic tadpoles carrying a doxycyline inducible dominant negative thyroid receptor transgene expressed exclusively in the muscle using a muscle specific promoter and identify the genes involved in the degenerative process . F1 progeny of transgenic Xenopus frogs and their nontransgenic siblings (at stages NF55 and NF66) were treated with 50µg doxycycline hyclate in 0.1 X MMR solution for 2 weeks or 6 weeks to induce the over-expression of the transgene. Limbs from the tadpoles were dissected at the end of the experiment. Keywords: development or differentiation design,reference design,replicate design,time series design
2006-07-08 | GSE5249 | GEO
Project description:Amphibians such as the salamanders and the African clawed frog Xenopus are great models for regeneration studies because they can fully regenerate their lost organs. While axolotl can regenerate damaged organs throughout its lifetime, Xenopus has a limited regeneration capacity after metamorphosis. The ecotropic viral integrative factor 5 (Evi5), a cell-cycle-regulated protein that prevents cells from entering mitosis prematurely, is of great interest for it is highly upregulated in the limb blastema of axolotls, but its expression level remains unchanged in the fibroblastema of postmetamorphic frogs. Yet, its role in regeneration competent context in Xenopus has not been fully analyzed. Here we show that Evi5 is also upregulated in Xenopus tadpoles after limb and tail amputation, as it is in axolotls. Down-regulation of Evi5 with morpholino antisense oligos (Mo) impairs wound healing and blastema formation in limbs and tails in both axolotls and Xenopus tadpoles, suggesting a conserved function for Evi5 in regeneration. Using skin punch as a healing model we show that Evi5 is also involved in cell migration during wound healing. RNA-sequencing analysis shows that in addition to reduced signaling of Lepr, Pdgfa, Gdf5, evi5 Mo also downregulate lysine demethylases kdm6b and kdm7a, which are also required for limb regeneration. Thus, our results demonstrate that Evi5 plays a critical role in the regeneration of multiple systems in amphibians.
2022-11-24 | GSE218034 | GEO