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Project description:Tissue regeneration is a process that recapitulates the molecular and mechanical aspects of development and evolution. We use the wound-induced hair neogenesis (WIHN) model to investigate the mechanical and molecular responses of the laboratory (Mus) and African spiny (Acomys) mice. Laboratory and spiny mice showed an opposite trend of spatiotemporal morphogenetic field for WIHN during wound healing, and wound stiffness gradient across the whole wound bed predicated pattern of hair formation. Using bulk and single-cell RNA-seq analysis and K14-Cre-Twist1 transgenic mice, we identified the central role of the Twist1 pathway as the mediator of epidermal-dermal interaction and the emergence of periodic hair primordia. Lastly, we generated a Turing model with an underlying measure of stiffness to support a two-scale tissue mechanic model to explain the setup of a morphogenetic field from a wound bed (mm scale) or periodically arranged hair primordia from a morphogenetic field (μm scale). Delineating the common and distinct chemo-mechanical events during regenerative wound healing between laboratory and African spiny mice reveal its evo-devo advantages, which provide new perspectives for regenerative medicine.
2023-10-23 | GSE159827 | GEO
Project description:Tissue regeneration is a process that recapitulates and restores organ structure and function. Although previous studies have demonstrated wound-induced hair neogenesis (WIHN) in laboratory mice (Mus), the regeneration is limited to the center of the wound unlike those observed in African spiny (Acomys) mice. Tissue mechanics have been implicated as an integral part of tissue morphogenesis. Here, we use the WIHN model to investigate the mechanical and molecular responses of laboratory and African spiny mice, and report these models demonstrate opposing trends in spatiotemporal morphogenetic field formation with association to wound stiffness landscapes. Transcriptome analysis and K14-Cre-Twist1 transgenic mice show the Twist1 pathway acts as a mediator for both epidermal-dermal interactions and a competence factor for periodic patterning, differing from those used in development. We propose a Turing model based on tissue stiffness that supports a two-scale tissue mechanics process: (1) establishing a morphogenetic field within the wound bed (mm scale) and (2) symmetry breaking of the epidermis and forming periodically arranged hair primordia within the morphogenetic field (μm scale). Thus, we delineate distinct chemo-mechanical events in building a Turing morphogenesis-competent field during WIHN of laboratory and African spiny mice and identify its evo-devo advantages with perspectives for regenerative medicine.
| S-EPMC8110808 | biostudies-literature
Project description:Tissue regeneration is a process that recapitulates the molecular and mechanical aspects of development and evolution. We use the wound-induced hair neogenesis (WIHN) model to investigate the mechanical and molecular responses of the laboratory (Mus) and African spiny (Acomys) mice. Laboratory and spiny mice showed an opposite trend of spatiotemporal morphogenetic field for WIHN during wound healing, and wound stiffness gradient across the whole wound bed predicated pattern of hair formation. Using bulk and single-cell RNA-seq analysis and K14-Cre-Twist1 transgenic mice, we identified the central role of the Twist1 pathway as the mediator of epidermal-dermal interaction and the emergence of periodic hair primordia. Lastly, we generated a Turing model with an underlying measure of stiffness to support a two-scale tissue mechanic model to explain the setup of a morphogenetic field from a wound bed (mm scale) or periodically arranged hair primordia from a morphogenetic field (μm scale). Delineating the common and distinct chemo-mechanical events during regenerative wound healing between laboratory and African spiny mice reveal its evo-devo advantages, which provide new perspectives for regenerative medicine.
2021-02-19 | GSE159938 | GEO
Project description:Symmetry breaking of tissue mechanics in wound induced hair follicle regeneration
| PRJNA670913 | ENA
Project description:Symmetry breaking of tissue mechanics in wound induced hair follicle regeneration [bulk RNA-seq]
| PRJNA670922 | ENA
Project description:RationaleLeft-right (LR) asymmetry is ubiquitous in animal development. Cytoskeletal chirality was recently reported to specify LR asymmetry in embryogenesis, suggesting that LR asymmetry in tissue morphogenesis is coordinated by single- or multi-cell organizers. Thus, to organize LR asymmetry at multiscale levels of morphogenesis, cells with chirality must also be present in adequate numbers. However, observation of LR asymmetry is rarely reported in cultured cells.ObjectivesUsing cultured vascular mesenchymal cells, we tested whether LR asymmetry occurs at the single cell level and in self-organized multicellular structures.Methods and resultsUsing micropatterning, immunofluorescence revealed that adult vascular cells polarized rightward and accumulated stress fibers at an unbiased mechanical interface between adhesive and nonadhesive substrates. Green fluorescent protein transfection revealed that the cells each turned rightward at the interface, aligning into a coherent orientation at 20° relative to the interface axis at confluence. During the subsequent aggregation stage, time-lapse videomicroscopy showed that cells migrated along the same 20° angle into neighboring aggregates, resulting in a macroscale structure with LR asymmetry as parallel, diagonal stripes evenly spaced throughout the culture. Removal of substrate interface by shadow mask-plating, or inhibition of Rho kinase or nonmuscle myosin attenuated stress fiber accumulation and abrogated LR asymmetry of both single-cell polarity and multicellular coherence, suggesting that the interface triggers asymmetry via cytoskeletal mechanics. Examination of other cell types suggests that LR asymmetry is cell-type specific.ConclusionsOur results show that adult stem cells retain inherent LR asymmetry that elicits de novo macroscale tissue morphogenesis, indicating that mechanical induction is required for cellular LR specification.
| S-EPMC3288887 | biostudies-literature
Project description:Background:Wound-induced hair follicle neogenesis (WIHN) is a phenomenon of hair neogenesis that occurs at the center of a scar when the wound area is sufficiently large. Neogenic hair follicles are separated from the pre-existing follicles at the wound edge by a hairless circular region. This WIHN study provides a unique model for developing treatments for hair loss and deciphering the mechanisms underlying organogenesis in adult mammals. Methods:The skin of a mouse was wounded by excising a 1.5 × 1.5 cm2 square of full-thickness dorsal skin. iTRAQ technology was used to screen proteins differentially expressed between the inner and outer scar areas in a mouse model of WIHN, on post-wounding day 15, to identify the regulators of WIHN. Owing to the overexpression of interleukin-36? (IL-36?) in the de novo hair follicle growth area, the regulating effect of IL-36? overexpression in WIHN was investigated. Hair follicle stem/progenitor cells were counted by flow cytometry while the expression of hair follicle stem/progenitor cell markers (Lgr5, Lgr6, Lrig1, K15, and CD34) and that of Wnt/?-catenin and IL-6/STAT3 pathway intermediaries was detected by qPCR and western blotting. Results:We found that wounding induced IL-36? expression. Incorporation of recombinant murine IL-36? (mrIL-36?) into murine skin wounds resulted in a greater number of regenerated hair follicles (p < 0.005) and a faster healing rate. The expression of hair follicle stem/progenitor cell markers was upregulated in the mrIL-36?-injected site (p < 0.05). Additionally, mrIL-36? upregulated the IL-6/STAT3 pathway intermediaries. Conclusion:IL-36? is upregulated in de novo hair follicle growth areas and can promote wound epithelialization and WIHN.
| S-EPMC7493638 | biostudies-literature
Project description:Upon wounding, multiple stem cell populations in the hair follicle (HF) and interfollicular epidermis (IFE) converge at the site of injury. Although these cells can contribute permanently to the regenerating epithelium, it remains unclear whether these contributions vary among cells originating from diverse compartments in the skin. By comparing the fates of several keratinocyte lineages, we observed here an initial decrease in both HF- and IFE-derived cells within the transient acanthotic layers of the regenerating epithelium. At the same time, the relative abundance of early-arriving IFE-derived cells specifically in the wound basal layer declined as later-arriving HF-derived cells entered the site of injury. Although laggard bulge-derived cells were typically constrained at the regenerative periphery, these cells persisted in the wound basal layer. Finally, suppressing Notch enabled IFE-derived cells to out-compete HF-derived cells. Taken together, these findings indicate that IFE-, HF- and bulge-derived cells make distinct contributions to regeneration over time. Furthermore, we speculate that extrinsic, non-genetic factors such as spatial constraint, distance from the wound, and basal versus suprabasal position may largely determine whether a cell ultimately persists.
| S-EPMC4825603 | biostudies-literature
Project description:Cutaneous wounds in adult mammals typically heal by scarring. However, large full-thickness wounds undergo wound-induced hair follicle neogenesis (WIHN), a form of regeneration. Here, we show that WIHN requires transient expression of epidermal Msx2 in two phases: the wound margin early and the wound center late. Msx2 expression is present in the migrating epithelium during early wound healing and then presents in the epithelium and mesenchyme later in the wound center. WIHN is abrogated in germline and epithelial-specific Msx2 mutant mice. Unlike the full-length Msx2 promoter, a minimal Msx2 promoter fails activation in the wound center, suggesting complex regulation of Msx2 expression. The Msx2 promoter binding sites include Tcf/Lef, Jun/Creb, Pax3, and three SMAD sites. However, basal epithelial-induced BMP suppression by noggin overexpression did not affect WIHN. We propose that Msx2 signaling is required for the epidermis to acquire spatiotemporal competence during WIHN. Topologically, hair regeneration dominates in the wound center, coinciding with late Msx2 expression. Together, these results suggest that intrinsic Msx2 expression supports epithelial competency during hair follicle neogenesis. This work provides insight into endogenous mechanisms modulating competency of adult epidermal progenitors for mammalian ectodermal appendage neogenesis, and offers the target Msx2 for future regeneration-promoting therapies.
| S-EPMC6109435 | biostudies-literature
Project description:New hair follicles (HFs) do not form in adult mammalian skin unless epidermal Wnt signalling is activated genetically or within large wounds. To understand the postnatal loss of hair forming ability we monitored HF formation at small circular (2 mm) wound sites. At P2, new HFs formed in back skin, but HF formation was markedly decreased by P21. Neonatal tail also formed wound-associated HFs, albeit in smaller numbers. Postnatal loss of HF neogenesis did not correlate with wound closure rate but with a reduction in Lrig1-positive papillary fibroblasts in wounds. Comparative gene expression profiling of back and tail dermis at P1 and dorsal fibroblasts at P2 and P50 showed a correlation between loss of HF formation and decreased expression of genes associated with proliferation and Wnt/β-catenin activity. Between P2 and P50, fibroblast density declined throughout the dermis and clones of fibroblasts became more dispersed. This correlated with a decline in fibroblasts expressing a TOPGFP reporter of Wnt activation. Surprisingly, between P2 and P50 there was no difference in fibroblast proliferation at the wound site but Wnt signalling was highly upregulated in healing dermis of P21 compared with P2 mice. Postnatal β-catenin ablation in fibroblasts promoted HF regeneration in neonatal and adult mouse wounds, whereas β-catenin activation reduced HF regeneration in neonatal wounds. Our data support a model whereby postnatal loss of hair forming ability in wounds reflects elevated dermal Wnt/β-catenin activation in the wound bed, increasing the abundance of fibroblasts that are unable to induce HF formation.
| S-EPMC4958333 | biostudies-literature