FGF8 induces bone and joint regeneration at middle phalanx amputation wounds in neonate mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE294048 | GEO | 2026/02/18
REPOSITORIES: GEO
Similar Datasets
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
Project description:In the mouse distal terminal phalanx (P3), it remains mystery why amputation at less than 33% of the digit results in regeneration, while amputation exceeding 67% leads to non-regeneration. Unraveling the molecular mechanisms underlying this disparity could provide crucial insights for regenerative medicine. In this study, we aim to investigate the tissues within the wound bed to understand the tissue microenvironment associated with regenerative versus non-regenerative outcomes. We employed a P3-specific amputation model in mice, integrated with time-series RNA-seq and a macrophage assay challenged with pro- and anti-inflammatory cytokines, to explore these mechanisms. Our findings revealed that non-regenerative digits exhibit a greater intense early transcriptional response in the wound bed compared to regenerative ones. Furthermore, early macrophage phenotypes differ distinctly between regenerative and non-regenerative outcomes. Regenerative digits also display unique co-expression modules related to Bone Morphogenetic Protein 2 (Bmp2). The differentially expressed genes (DEGs) between regenerative and non-regenerative digits are enriched in targets of several transcription factors, such as HOXA11 and HOXD11 from the HOX gene family, showing a time-dependent pattern of enrichment. These transcription factors, known for their roles in bone regeneration, skeletal patterning, osteoblast activity, fracture healing, angiogenesis, and key signaling pathways, may act as master regulators of the regenerative gene signatures. Additionally, we developed a deep learning AI model capable of predicting post-amputation time and level from RNA-seq data, indicating that the regenerative probability may be "encoded" in the transcriptomic response to amputation.
2025-03-26 | GSE279540 | GEO
Project description:Mammalian digit-tip can regenerate upon amputation1-3, like amphibians. It is unknown why this capacity is limited to the area associated with the nail3-5. Here, we show that nail stem cells (NSCs) reside in the Wnt-suppressed proximal nail matrix and that the mechanisms governing NSC differentiation are directly coupled with their ability of orchestrating digit regeneration. Early nail progenitors located distal to the NCS region undergo Wnt-dependent differentiation into nail. Upon amputation, this Wnt activation is required for nail regeneration and also for attracting nerves that promote mesenchymal blastema growth, leading to regeneration of the entire digit. Amputations proximal to the Wnt-active nail progenitors result in failure to regenerate nail/digit. Nevertheless, β-catenin stabilization in the NSC region induced their regeneration. These results establish a link between NCS differentiation and digit regeneration, suggesting a utility of the NSCs in developing novel treatments for amputees. Nail matrix cells were harvested from proximal and distal matrix region by microdissection and processed to RNA extraction and hybridization on Affymetrix microarrays. We analyzed two proximal and two distal matrix cells.
2013-03-27 | E-GEOD-45494 | biostudies-arrayexpress
Project description:Although mammals generally demonstrate limited regenerative capacity compared with amphibians, the digit tip retains remarkable regenerative potential, providing a useful model to study successful mammalian regeneration. This process involves coordinated immune cell activity, vascular remodeling, and tissue reconstruction, yet the molecular checkpoints controlling regenerative versus fibrotic outcomes remain poorly understood. In mammals, regeneration of the digit tip (P3) proceeds through myeloid cell migration, early osteoclast-mediated osteolysis of the distal bone, and subsequent blastema-mediated regeneration. Here we test the hypothesis that lymphatic vessels regulate regenerative capacity by modulating local immune cell dynamics and osteoclast function. Using a lymphatic system–specific reporter line, we discovered that lymphatic vessels grow toward the nail region from the ventral side of the digit during quiescence and after amputation. These lymphatics closely surround, but do not invade, the native or regenerated bone. Unexpectedly, genetic, pharmacological, and surgical inhibition of lymphangiogenesis accelerated early osteolysis through enhanced transition of myeloid cells to osteoclasts, resulting in faster and more robust regeneration. These findings reveal a mechanism linking lymphatic vessel, immune regulation, and bone remodeling, suggesting that targeted manipulation of lymphatics dynamics may enhance regenerative outcomes after musculoskeletal injury.
2026-02-06 | GSE313923 | GEO
Project description:Mammalian digit-tip can regenerate upon amputation1-3, like amphibians. It is unknown why this capacity is limited to the area associated with the nail3-5. Here, we show that nail stem cells (NSCs) reside in the Wnt-suppressed proximal nail matrix and that the mechanisms governing NSC differentiation are directly coupled with their ability of orchestrating digit regeneration. Early nail progenitors located distal to the NCS region undergo Wnt-dependent differentiation into nail. Upon amputation, this Wnt activation is required for nail regeneration and also for attracting nerves that promote mesenchymal blastema growth, leading to regeneration of the entire digit. Amputations proximal to the Wnt-active nail progenitors result in failure to regenerate nail/digit. Nevertheless, β-catenin stabilization in the NSC region induced their regeneration. These results establish a link between NCS differentiation and digit regeneration, suggesting a utility of the NSCs in developing novel treatments for amputees.
2013-03-27 | GSE45494 | GEO
Project description:The salamander has the remarkable ability to regenerate its limb after amputation. Cells at the site of amputation form a blastema and then proliferate and differentiate to regrow the limb. To better understand this process, we have performed deep RNA sequencing of the blastema over a time course. We find genes expressed in three phases with a prominent burst in oncogene expression during the first day, blastemal/limb bud genes peaking at 7 to 14 days, and markers for terminal differentiation upregulated later. We compare these expression patterns to those in a mouse digit amputation model to identify genes specific to the regenerative response. We find that limb patterning genes, SALL genes, and genes involved in the proteasome, adult stem cell, embryonic stem cell, retinoid metabolism, and WNT and NOTCH signaling are regeneration-specific. We establish the “Axolomics” Database, which provides a tool for depositing, retrieving, and searching axolotl-related “omic” information. The experiment includes two time course data sets. One is from mouse digit amputation, another is from Axolotl digit amputation
2013-09-01 | E-GEOD-34394 | biostudies-arrayexpress
Project description:Mice were subjected to hindlimb distal phalanx (P3) amputation to digit 3. For each amputation, mice were anesthetized, the hindlimb claw was extended, and the distal phalanx and footpad was sharply dissected. A regenerating distal phalanx was generated by amputating ≤33% of the P3. Skin wounds were allowed to heal without suturing. Mice were subjected to micro-computed tomography (microCT) one day prior to surgery and immediately after amputation to confirm ≤ 33% removal of the P3. Any digit that did not fall within the ≤ 33% amputation guideline was omitted from the study. Based on our criteria, 17 animals were removed from the study resulting in a final total of 30 mice. P3 mice were collected at hours (0h, 3h, 6h ,12h, and 24h), and days (3d, 7d, 14d, and 21d). Each time point contained 3 mice, except day 7 (6 mice). At the time of P3 collection, samples were immediately immersed in RNAlater for 24h at 4C. The digits were then removed from RNAlater and stored at -80C until performing RNA sequencing.
2020-02-19 | GSE130438 | GEO
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
Project description:De novo limb regeneration after amputation is restricted in mammals to the distal digit tip. Central to this regenerative process is the blastema, a heterogeneous population of lineage-restricted, dedifferentiated cells that ultimately orchestrates the regeneration of the amputated bone and surrounding soft tissue. To investigate skeletal regeneration, we made use of spatial transcriptomics to characterize the transcriptional profile specifically within the blastema. Using this technique, we generated a gene signature with high specificity for the blastema in both our spatial data, as well as other previously published single-cell RNA-sequencing transcriptomic studies. To elucidate potential mechanisms distinguishing regenerative from non-regenerative healing, we applied spatial transcriptomics to an aging model. Consistent with other forms of repair, our digit amputation mouse model showed a significant impairment in regeneration in aged mice. Contrasting young and aged mice, spatial analysis revealed a metabolic shift in aged blastema associated with an increased bioenergetic requirement. This enhanced metabolic turnover was associated with increased hypoxia and angiogenic signaling, leading to excessive vascularization and altered regenerated bone architecture in aged mice. Restoration of this metabolic deficiency using the metabolite oxaloacetate enhanced in vivo bone regeneration. Thus, targeting cell metabolism may be a promising strategy to mitigate aging-induced declines in tissue regeneration.
2022-06-01 | GSE180682 | GEO
Project description:Variability of regenerative potential among animals has long perplexed biologists. Based on their amazing regenerative abilities, planarians have become important models for understanding the molecular basis of regeneration; however, planarian species with limited regenerative abilities are also found. Despite the importance of understanding the differences between closely related, regenerating and non-regenerating organisms, few studies have focused on the evolutionary loss of regeneration, and the molecular mechanisms leading to such regenerative loss remain obscure. Here we examine Procotyla fluviatilis, a planarian with restricted ability to replace missing tissues, utilizing next-generation sequencing to define the gene expression programs active in regeneration-permissive and regeneration-deficient tissues. We found that Wnt signaling is aberrantly activated in regeneration-deficient tissues. Remarkably, down-regulation of canonical Wnt signaling in regeneration-deficient regions restores regenerative abilities: blastemas form and new heads regenerate in tissues that normally never regenerate. This work reveals that manipulating a single signaling pathway can reverse the evolutionary loss of regenerative potential. RNA-seq experiments to identify gene expression changes following amputation in body regions with variable regenerative potential. Adult Procotyla fluviatilis were amputated at sites either anterior or posterior to the pharynx. After 24 hours post-amputation, tissues near the amputation site were excised and RNA was extracted. Similar tissues were excised from uncut control animals. Samples were processed for RNA-seq using Illumina procedures. We generated a de novo P. fluviatilis transcriptome and used RNA sequencing (RNA-seq) to characterize transcripts from excised tissue fragments in Reg+ and Reg- body regions 24 hours post-amputation. We performed parallel analyses on tissues excised from intact animals at identical body regions to account for regional differences in transcripts, thereby identifying changes resulting from amputation. Samples A1-A3 = Regeneration-proficient (Reg+) tissue excision 24 hours after amputation. Samples B1-B3 = Tissue excision from regeneration-proficient (Reg+) region but not amputated. Samples C1-C3 = Tissue excision from regeneration-deficient (Reg-) tissues 24 hours after amputation. Samples D1, D3-D4 = Tissue excision from regeneration-deficient (Reg-) region that was not amputated.
2013-07-04 | E-GEOD-48497 | biostudies-arrayexpress