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Symmetry breaking of tissue mechanics in wound induced hair follicle regeneration [scRNA-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE159827 | GEO | 2023/10/23

REPOSITORIES: GEO

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Symmetry breaking of tissue mechanics in wound induced hair follicle regeneration [bulk RNA-seq]

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

mice，skin, iTRAQ

Project description:Wound Induced Hair Follicle neogenesis (WIHN) is a hair neogenesis phenomenon which occurred in the center of scar. Neonatal hair follicle are separated from the preexisting follicles by a hairless circular. We analysed the differentially expressed proteins between inner and outer area of scar at post-wound day 15 by iTRAQ technology.

2021-09-08 | PXD012868 | Pride

Gene expression in normal human epidermal keratinocytes treated with poly(I:C)

Project description:In a rare example akin to organogenesis in adult mammals, large wounds in mice lead to de novo morphogenesis of hair follicles. It is still not fully clear what controls this process, known as Wound Induced Hair Neogenesis (WIHN). In other tissues, prostaglandin E2 (PGE2) is an important effector of regeneration and has been shown to stimulate the Wnt/beta-catenin pathway, which in turn is known to control WIHN. Previously, our group has demonstrated that noncoding dsRNA released during wounding is both necessary and sufficient to stimulate WIHN through TLR3. Here, we hypothesize that dsRNA similarly induces the beta-catenin pathway through PGE2. We find that WIHN levels correlate closely to Wnt7b production in vivo, and that dsRNA potently induces Wnt7b in a manner that requires prostaglandin-endoperoxide synthase 2 (Ptgs2). The Ptgs2 inhibitor celecoxib reduces dsRNA-induced WIHN and Wnt7b, and exogenous PGE2 can rescue WIHN and Wnt7b. These results highlight noncoding dsRNA as a novel upstream coordinator of prostaglandin and Wnt levels in regeneration. We used microarrays to identify the human keratinocyte genes most upregulated or downregulated by poly(I:C)

2017-04-17 | GSE92646 | GEO

Single cell RNA-seq analyses of dermis from wound day 18 large skin wounds that healed in a fibrotic or regenerative fashion.

Project description:Human and murine skin wounding commonly result in fibrotic scarring but the murine wounding model Wound Induced Hair Neogenesis (WIHN) can frequently result in a regenerative repair response. Here we show in single cell RNA-seq comparisons of semi-regenerative and fibrotic WIHN wounds, increased expression of phagocytic/lysosomal genes in macrophages associated with predominance of fibrotic myofibroblasts in fibrotic wounds. Investigation revealed that macrophages in the late wound drive fibrosis by phagocytizing dermal Wnt inhibitor SFRP4 to establish persistent Wnt activity. In accordance, phagocytosis abrogation resulted in transient Wnt activity and a more regenerative healing. Phagocytosis of SFRP4 was integrin-mediated and dependent on the interaction of SFRP4 with the EDA splice variant of fibronectin. In the human skin condition Hidradenitis suppurativa, phagocytosis of SFRP4 by macrophages correlated with fibrotic wound repair. These results reveal that macrophages can modulate a key signaling pathway via phagocytosis to alter the skin wound healing fate.

2019-12-12 | GSE141814 | GEO

Vaseline and Neosporin treated human popliteal fossae (PF) skin wound bed

Project description:Environmental factors that enhance regeneration are largely unknown. We hypothesized that skin bacteria modulate regeneration. Here, we assessed low, medium, and high levels of bacterial burden in Wound Induced Hair follicle Neogenesis (WIHN), a rare adult organogenesis model. WIHN levels and stem cell markers indeed correlated with bacterial counts, being lowest in germ free (GF), intermediate in conventional specific pathogen free (SPF), and highest even in mice infected with pathogenic Staphylococcus aureus. We identified IL-1β and keratinocyte-dependent IL-1R-MyD88 signaling as necessary and sufficient for bacteria to promote regeneration. Finally, in a small clinical trial, we found that a topical broad-spectrum antibiotic slowed skin wound healing. These results counter conventional notions that infection inhibits regeneration and the need for full sterility of small wounds.

2021-04-01 | GSE158616 | GEO

Expression data from Staphylococcus aureus and Phosphate buffered saline (PBS) treated mouse wound bed

2021-04-01 | GSE158614 | GEO

Expression data from germ free (GF) and specific pathogen free (SPF) mouse wound bed

2021-04-01 | GSE158613 | GEO

Expression data from the dermis of human stretched scars and patient-matched healthy dermis from occipital scalps

Project description:It is well accepted that elevated mechanical tension of the skin surrounding a healing wound stimulates a fibrotic cascade of events and contributes to an increased size of scars. A laxity paradox in the field of hair transplantation describes a phenomenon opposing this view. During Strip Follicular Unit Transplantation (Strip FUT), surgeons remove a strip of scalp skin (approximately 5 cm x 10 cm, depending on the number of hair follicles required) from the occipital scalp, which is then used to harvest hair follicles that will be transplanted into the balding frontal scalp. Most patients with normal scalp skin laxity heal with narrow normotrophic scars, while a small number of patients (14%) with very loose scalp skin, and so low residual skin tension, heal with post operating scar widening (4 - 12 mm). These scars, referred to as stretched scars in the hair transplantation field, often require revision surgery or secondary hair grafting into the scar. We hypothesise that stretched scars present a unique transcriptional signature different from other types of scars. To determine the gene expression profile of stretched scars, we used Affymetrix microarrays to perform profiling of fibrotic dermis and the surrounding patient-matched healthy dermis.

2022-12-31 | GSE162904 | GEO

Noncoding dsRNA induces retinoic acid synthesis to stimulate hair follicle regeneration via TLR3

Project description:This SuperSeries is composed of the SubSeries listed below. How developmental programs reactivate in regeneration is a fundamental question in biology. We addressed this question through the study of Wound Induced Hair follicle Neogenesis (WIHN), an adult organogenesis model where stem cells regenerate de novo hair follicles following deep wounding. The exact mechanism is uncertain. Here we show that self-noncoding dsRNA activates the anti-viral receptor toll like receptor 3 (TLR3) to induce intrinsic retinoic acid (RA) synthesis in a pattern that predicts new hair follicle formation after wounding in mice. Additionally, in humans, rejuvenation lasers induce gene expression signatures for dsRNA and RA, with measurable increases in intrinsic RA synthesis. These results demonstrate a potent stimulus for RA synthesis by non-coding dsRNA, relevant to their broad functions in development and immunity.

2019-05-22 | GSE128868 | GEO

In vivo gene signature of re-epithelialized tissue post-wounding from wildtype or Rnasel KO mice

Project description:Mammalian injury responses are characterized by fibrosis and scarring rather than the functional regeneration observed in other phyla. Limited regenerative capacity in mammals could reflect a loss of pro-regeneration programs or active suppression by genes functioning akin to tumor suppressors. To uncover programs governing regeneration in mammals, we investigated Wound Induced Hair Neogenesis (WIHN), a rare example of regeneration in adult mammals1,2. Through comprehensive screening of transcripts associated with both WIHN and human facial rejuvenation after laser treatment, we found the endoribonuclease RNase L to be a powerful suppressor of regeneration. Rnasel-/- mice exhibit remarkable regenerative capacity and accelerated wound healing following injury through the production of IL-36α. Consistent with the known role of RNase L to stimulate caspase-1 signaling, we find that pharmacologic inhibition of caspases promotes regeneration in an IL-36-dependent manner. These responses are not limited to skin but occur following intestinal injury as well, suggesting that suppression of regeneration is a general characteristic of mammalian wound healing. Taken together, this work suggests a therapeutic strategy to uncover latent regenerative capacity and promote functional response to injury. Biopsies of re-epithelialized tissue were recovered from wild-type or Rnasel KO mice approximately 10 days after wounding. Total RNA was extracted and sent for microarray analysis.

2021-11-18 | GSE164003 | GEO

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