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Enhancer-directed gene delivery for digit regeneration based on conserved epidermal factors [scRNA-seq]

ABSTRACT: Limb loss remains a significant clinical challenge, but regenerative medicine approaches such as gene therapy offer a promising strategy to trigger endogenous regeneration programs. Optimal vector configurations and molecular targets for appendicular skeletal repair are not well defined. Here, we leveraged insights from species with a high endogenous capacity for appendage regeneration to design an enhancer-directed gene delivery platform that functions during mouse digit regeneration, a well characterized model for partial limb regeneration in mammals. Single-cell RNA sequencing of zebrafish caudal fin regeneration, combined with expression data in regenerating salamander limbs and mouse digit tips, implicated the SP family of transcription factors as conserved, epidermally-expressed mediators of appendage regrowth. Null mutants of Sp8 demonstrated impaired limb regeneration in salamanders, while conditional knockout of Sp6 and/or Sp8 in the mouse basal epidermis resulted in defective bony digit tip regeneration, involving an IL-17 mediated osteoclastogenic program. Spatiotemporally focused expression of FGF8, a known target of SP factors, using a zebrafish-derived tissue regeneration enhancer element via adeno-associated viral vectors, could partially rescue digit tip regeneration in SP knockout mice and accelerate digit regeneration in wildtype mice. Our results demonstrate a contextual gene therapy approach to address limb loss based on genes like Sp transcription factors conserved across multiple contexts of appendage regeneration.

ORGANISM(S): Danio rerio

PROVIDER: GSE309821 | GEO | 2026/04/06

REPOSITORIES: GEO

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Enhancer-directed gene delivery for digit regeneration based on conserved epidermal factors

Project description:Limb loss remains a significant clinical challenge, but regenerative medicine approaches such as gene therapy offer a promising strategy to trigger endogenous regeneration programs. Optimal vector configurations and molecular targets for appendicular skeletal repair are not well defined. Here, we leveraged insights from species with a high endogenous capacity for appendage regeneration to design an enhancer-directed gene delivery platform that functions during mouse digit regeneration, a well characterized model for partial limb regeneration in mammals. Single-cell RNA sequencing of zebrafish caudal fin regeneration, combined with expression data in regenerating salamander limbs and mouse digit tips, implicated the SP family of transcription factors as conserved, epidermally-expressed mediators of appendage regrowth. Null mutants of Sp8 demonstrated impaired limb regeneration in salamanders, while conditional knockout of Sp6 and/or Sp8 in the mouse basal epidermis resulted in defective bony digit tip regeneration, involving an IL-17 mediated osteoclastogenic program. Spatiotemporally focused expression of FGF8, a known target of SP factors, using a zebrafish-derived tissue regeneration enhancer element via adeno-associated viral vectors, could partially rescue digit tip regeneration in SP knockout mice and accelerate digit regeneration in wildtype mice. Our results demonstrate a contextual gene therapy approach to address limb loss based on genes like Sp transcription factors conserved across multiple contexts of appendage regeneration.

2026-04-06 | GSE309792 | GEO

Sp8 regulatory function in the limb bud ectoderm [RNA-seq]

Project description:Sp8 and Sp6, members of the Sp family of transcription factors, are required in a dose-dependent manner to induce Fgf8 and En1 in the limb bud ectoderm, therefore controlling proximo-distal and dorso-ventral limb development. Mouse genetics revealed that Sp8 makes a much greater contribution than Sp6 but the nature of its regulatory mechanism was unknown. Here, by combining ChIP-seq and RNA-seq genome-wide analyses we show that Sp8 predominantly functions as an activator from putative distal enhancers regulating crucial limb patterning genes and underscoring its master role in limb development. We also provide compelling evidence for Sp8 cooperating with Dlx5 for the regulation of a considerable set of its target genes. Our work supports a model in which Sp8, Sp6 and Dlx5 act conjointly to regulate target genes with a final functional outcome that depends on their relative availability. This should be considered when interpreting Sp and Dlx mutant phenotypes.

2021-02-01 | GSE144732 | GEO

Sp8 regulatory function in the limb bud ectoderm [ChIP-seq]

2021-02-01 | GSE144731 | GEO

Single cell RNA sequencing of adult regenerating mouse digit tips

Project description:Innate regeneration following digit tip amputation is one of the few examples of epimorphic regeneration in mammals. Digit tip regeneration is mediated by the blastema, the same structure invoked during limb regeneration in some lower vertebrates. By genetic lineage analyses in mice, the digit tip blastema has been defined as a population of heterogeneous, lineage restructed progenitor cells. These previous studies, however, do not comprehensively evaluate blastema heterogeneity or address lineage restruction of closely related cell types. Here we report single cell RNA sequencing of over 38,000 cells from mouse digit tip blastemas and unamputated control digit tips and generate an atlas of the cell types participating in digit tip regeneration.

2020-02-24 | GSE143888 | GEO

Single cell RNA sequencing of adult regenerating mouse digit tips

Project description:Innate regeneration following digit tip amputation is one of the few examples of epimorphic regeneration in mammals. Digit tip regeneration is mediated by the blastema, the same structure invoked during limb regeneration in some lower vertebrates. By genetic lineage analyses in mice, the digit tip blastema has been defined as a population of heterogeneous, lineage restructed progenitor cells. These previous studies, however, do not comprehensively evaluate blastema heterogeneity or address lineage restruction of closely related cell types. Here we report one additional single cell RNA sequencing sample (28 days post-amputation) to add to our already published 38,000 cells from mouse digit tip blastemas and unamputated control digit tips used to generate an atlas of the cell types participating in digit tip regeneration.

2024-07-03 | GSE267446 | GEO

Sensory nerve input is not required for digit tip regeneration

Project description:Peripheral nerves are a major component of the post-injury microenvironment and are required for successful appendage regeneration in non-mammalians. However, the role of innervation in mouse digit tip regeneration is unclear. We developed a denervation technique that maintains mechanical loading while significantly reducing innervation to the digit. Using this model, we found that denervation does not impair digit tip regeneration. Histological analysis showed the amputation stump proceeds through the expected phases of wound healing, blastema formation, and tissue outgrowth, and that regenerate bone volume is not significantly impaired in denervated digits. Interestingly, despite minimal change in regenerative outcome, bulk RNA sequencing identified significant changes in gene expression over time during regeneration in the absence of innervation. This study is the first to use RNA sequencing to characterize changes in gene expression during digit tip regeneration in the absence of innervation. Overall we show that digit tip regeneration is not dependent on innervation and our results suggest that regeneration may be achieved through activation of redundant signalling pathways.

2026-04-01 | GSE325460 | GEO

Acquisition of a unique mesenchymal precursor-like blastema state underlies successful adult mammalian digit tip regeneration

Project description:Here, we investigate the origin and nature of blastema cells that regenerate the adult murine digit tip. We show that Pdgfra-expressing mesenchymal cells in uninjured digits establish the regenerative blastema and are essential for regeneration. Single cell profiling shows that the mesenchymal blastema cells are distinct from both uninjured digit and embryonic limb/digit Pdgfra-positive cells. This unique blastema state is environmentally determined; dermal fibroblasts transplanted into the regenerative, but not non-regenerative, digit express blastema markers and contribute to bone regeneration. Moreover, lineage tracing with single cell profiling indicates that endogenous osteoblasts/osteocytes acquire a blastema mesenchymal transcriptional state and contribute to both dermis and bone regeneration. Thus, mammalian digit tip regeneration occurs via a distinct adult mechanism where the regenerative environment promotes acquisition of a unique blastema state that allows cells from tissues like bone to contribute to regeneration of other mesenchymal tissues such as the dermis.

2019-11-15 | GSE135985 | GEO

Transcriptomic analysis of bone and fibrous tissue morphogenesis during digit tip regeneration in the adult mouse

Project description:Purpose: Investigate the transcriptomic landscape throughout the time course of murine digit regeneration after level-dependent amputation. Methods: The terminal phalanx bone of hind limb digits was subjected to either a distal amputation (25% bone length loss) or proximal amputation (65% bone length loss). Total RNA was isolated from bone and fibrous tissues distal to the distal interphalangeal joint at 12, 14, and 21 days post-amputation (DPA). mRNA library was sequenced using Illumina HiSeq 3000. Trimmed reads were aligned to the mouse genome mm10 and batch-corrected. Results: A limb-specific developmental signaling pathway is transiently upregulated at 14 DPA after distal amputation, corresponding with regeneration of digit tip tissues. Absence of a limb-specific pathway after proximal amputation corresponded with minimal regeneration and fibrotic scarring. Conclusions: Digit regeneration is a level-dependent and spatiotemporally controlled process, with distal and proximal amputations showing significant differences in gene expression and tissue regrowth over time.

2020-06-10 | GSE131078 | GEO

Failure of digit tip regeneration in the absence of Lmx1b suggests Lmx1b functions disparate from dorsoventral polarity

Project description:Mammalian digit tip regeneration is linked to the presence of nail tissue, but a nail-explicit model is missing. Here, we report that nail-less double-ventral digits of ΔLARM1/2 mutants that lack limb-specific Lmx1b enhancers, fail to regenerate. To separate the nail’s effect from the lack of DV polarity, we also interrogate double-dorsal double-nail digits and show that they regenerate. Thus, DV polarity is not a prerequisite for regeneration and the nail requirement is supported. Transcriptomic comparison between wild-type and non-regenerative ΔLARM1/2 mutant blastemas reveals differential up-regulation of vascularization and connective tissue functional signatures in wild-type versus upregulation of inflammation in the mutant. These results, together with the finding of Lmx1b expression in the postnatal dorsal dermis underneath the nail and uniformly in the regenerative blastema opens the possibility of additional Lmx1b roles in the progression of digit tip regeneration, in addition to the indirect effect of mediating the formation of the nail.

2022-12-02 | GSE202223 | GEO

FGF8 induces bone and joint regeneration at middle phalanx amputation wounds in neonate mice

Project description:Mice and humans have limited regenerative capacity following limb amputation, with regenerative responses restricted to amputations transecting the distal digit tip, (P3). Unlike P3, amputations of the adjacent skeletal segment, the middle phalanx, P2, are non-regenerative. Here, we report that FGF8 drives synovial joint regeneration at P2 amputation wounds in neonate mice. This response is characterized by the regeneration of a synovial cavity, a skeletal nodule lined with articular-like cartilage, tendon and ligament regeneration, and partial P2 stump regeneration. FGF8-induced joint regeneration is associated with the upregulation of several, but not all, genes that characterize joint development, and is morphologically distinct from digit joint development. Lineage tracing studies demonstrate that cells at the amputation wound contribute to the regenerated joint structures. These studies provide evidence that the otherwise non-regenerative P2 amputation wound possesses tremendous regenerative capacity that is not activated under normal circumstances.

2026-02-18 | GSE294048 | GEO

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