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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE135985 | GEO | 2019/11/15

REPOSITORIES: GEO

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Mesenchymal precursor cells in adult nerves contribute to mammalian tissue repair and regeneration

Project description:Peripheral innervation plays an important role in regulating tissue repair and regeneration. Here, we provide evidence that injured peripheral nerves provide a reservoir of mesenchymal precursor cells that can directly contribute to murine digit tip regeneration and skin repair. In particular, using single-cell RNA sequencing and lineage tracing we identify transcriptionally-distinct mesenchymal cell populations within the control and injured adult nerve, including neural crest-derived cells in the endoneurium with characteristics of mesenchymal precursor cells. Culture and transplantation studies show that these nerve-derived mesenchymal cells have the potential to differentiate into non-nerve lineages. Moreover, following digit tip amputation, the neural crest-derived nerve mesenchymal cells contribute to the regenerative blastema and ultimately to the regenerated bone. Similarly, neural crest derived nerve mesenchymal cells contribute to the dermis during skin wound healing. These findings support a model where peripheral nerves directly contribute mesenchymal precursor cells to promote repair and regeneration of injured mammalian tissues.

2018-11-29 | GSE120678 | 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

Nail-associated mesenchymal cells contribute to and are essential for dorsal digit tip regeneration

Project description:Here, we have asked why the nail base is essential for mammalian digit tip regeneration, focusing on the inductive nail mesenchyme. We identify a transcriptional signature for these cells that includes Lmx1b, and show that the Lmx1b-expressing nail mesenchyme is essential for blastema formation. We use a combination of Lmx1bCreERT2-based lineage tracing and single cell transcriptional analyses to show that the nail mesenchyme contributes cells for two pro-regenerative mechanisms. One group of cells maintains their identity and regenerates the new nail mesenchyme. A second group contributes specifically to the dorsal blastema, loses their nail mesenchyme phenotype, acquires a blastema transcriptional state that is highly similar to blastema cells of other origins and ultimately contributes to regeneration of the dorsal but not ventral dermis and bone. Thus, the regenerative necessity for an intact nail base is explained, at least part by a requirement for the inductive nail mesenchyme.

2022-11-16 | GSE217600 | GEO

Spatial transcriptomics reveals increased energetic requirements underpinning age-dependent declines in digit regeneration rescued through administration of OAA

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

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

Nerve-derived Schwann cell precursors, acting in a paracrine fashion, are essential for mammalian digit tip regeneration [RAT]

Project description:Multi-tissue regenerative capacity is lost in adult mammals with the exception of the distal digit, which regenerates via largely-uncharacterized mechanisms. Here, we demonstrate that following adult mouse distal digit removal, nerve-associated Schwann cell precursors (N-SCPs) dedifferentiate and secrete growth factors that promote expansion of the blastema and digit regeneration. Specifically, when N-SCPs were dysregulated or ablated, mesenchymal precursor proliferation in the blastema was decreased, nail and bone regeneration were impaired, and regeneration could be rescued by transplantation of exogenous N-SCPs. We show that N-SCPs secreted factors that promoted self-renewal of mesenchymal precursors, and we used transcriptomic and proteomic analysis to define candidate factors. Two of these, oncostatin M (OSM) and PDGF-AA, were made by N-SCPs in the regenerating digit, and rescued the deficits in regeneration caused by loss of N-SCPs due to denervation. Since nerves innervate every peripheral tissue, these results have broad implications for mammalian tissue repair and regeneration.

2016-07-12 | GSE81703 | GEO

Nerve-derived Schwann cell precursors, acting in a paracrine fashion, are essential for mammalian digit tip regeneration [MOUSE]

2016-07-12 | GSE81697 | GEO

Expression analysis of nail matrix in mouse.

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, Î²-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

Expression analysis of nail matrix in mouse.

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

Three Distinct Phases of Regeneration-Specific Gene Expression in the Axolotl Blastema

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

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