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Clearance of p21-highly-expressing senescent cells accelerates wound healing

ABSTRACT: Targeting senescent cells for therapeutic purposes is gaining momentum across various organ systems. However, concerns about potential off-target effects have been raised. Previous studies have shown that removing senescent cells expressing high levels of p16 (p16high) can hinder processes like wound healing. Here, we identify a distinct senescent cell population during dermal wound healing characterized by high expression level of p21 (p21high) using the p21-Cre mouse model. Using a standard cutaneous injury model, we find that eliminating p21high cells can expedite wound closure, in contrast to the effects of removing p16high cells. Through Xenium, a single cell spatial imaging platform, we show that p21high cells are distinct from p16high cells, with p21high cells mainly comprising fibroblasts, immune cells, keratinocytes, and endothelial cells with a pro-inflammatory profile. Moreover, inhibition of NF-kB signaling specifically from p21high cells partially contributes to the accelerated wound healing rates. These findings highlight the heterogeneity of senescent cells during wound healing responses within the skin and likely in other conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE278611 | GEO | 2024/10/07

REPOSITORIES: GEO

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Clearance of p21-highly-expressing senescent cells accelerates cutaneous wound healing

Project description:Targeting senescent cells for therapeutic purposes is gaining momentum across various organ systems. However, concerns about potential off-target effects have been raised. Previous studies have shown that removing senescent cells expressing high levels of p16 (p16high) can hinder processes like wound healing. Here, we identify a distinct senescent cell population during dermal wound healing characterized by high expression level of p21 (p21high) using the p21-Cre mouse model. Using a standard cutaneous injury model, we find that eliminating p21high cells can expedite wound closure, in contrast to the effects of removing p16high cells. Through Xenium, a single cell spatial imaging platform, we show that p21high cells are distinct from p16high cells, with p21high cells mainly comprising fibroblasts, immune cells, keratinocytes, and endothelial cells with a pro-inflammatory profile. Moreover, inhibition of NF-kB signaling specifically from p21high cells partially contributes to the accelerated wound healing rates. These findings highlight the heterogeneity of senescent cells during wound healing responses within the skin and likely in other conditions.

2024-10-01 | GSE278527 | GEO

Clearance of p21-highly-expressing senescent cells accelerates wound healing

Project description:Clearance of p21-highly-expressing senescent cells accelerates wound healing

| PRJNA1168086 | ENA

Clearance of p21-highly-expressing senescent cells accelerates cutaneous wound healing

Project description:Clearance of p21-highly-expressing senescent cells accelerates cutaneous wound healing

| PRJNA1167732 | ENA

Defined p16High senescent cell types are indispensable for mouse healthspan

Project description:The accumulation of senescent cells can drive many age-associated phenotypes and pathologies. Consequently, it has been proposed that removing senescent cells might extend lifespan. Here we generated two knock-in mouse models targeting the best-characterized marker of senescence, p16Ink4a. Using a genetic lineage tracing approach, we found that age-induced p16High senescence is a slow process that manifests around 10-12 months of age. The majority of p16High cells were vascular endothelial cells mostly in liver sinusoids (LSECs), and to lesser extent macrophages and adipocytes. In turn, continuous or acute elimination of p16High senescent cells disrupted blood–tissue barriers with subsequent liver and peri-vascular tissue fibrosis and health deterioration. Our data show that senescent LSECs are not replaced after removal and have important structural and functional roles in the aging organism. In turn, delaying senescence or replacement of senescent LSECs could represent a powerful tool in slowing down aging.

2020-01-01 | GSE125439 | GEO

Cellular and functional characterization of aging-independent senescent-like cells that modulate tissue repair

Project description:Cells expressing features of cellular senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Using skeletal fracture as a model of acute injury, we identified rapidly-appearing senescent-like cells, marked by p21 expression, that negatively affected fracture healing. p21+ callus cells, which consisted predominantly of neutrophils and osteochondroprogenitors, existed as transient cells specific to injury and expressed high levels of senescence-associated factors known to impair bone formation and induce paracrine senescence. Targeted genetic clearance of p21+ cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, p21+ cell clearance did not alter bone loss due to aging; conversely, p16+ cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Together, our findings establish contextual roles of senescent/senescent-like cells that may be leveraged for therapeutic opportunities.

2024-06-20 | GSE253863 | GEO

ANKRD1 promotes cell migration by suppressing ELN production during early senescence

Project description:Cellular senescence is a complex biological process that contributes to wound healing, carcinogenesis, and age-related disease. Although the molecular mechanisms whereby senescence promotes wound repair are not well understood, the protein ANKRD1, which promoted wound healing in mice, was found to increase in senescent cells. We hypothesized that ANKRD1 may play a role in senescence-mediated wound healing. Conditioned medium (CM) from senescent WI-38 human diploid fibroblasts hastened cell migration of human HaCaT keratinocytes. Interestingly, silencing ANKRD1 in WI-38 cells reduced the effect of CM on cell migration, while overexpressing ANKRD1 accelerated it. Further proteomic analysis revealed that ANKRD1 associates with YBOX1, a multifunctional protein that modulates transcription of the ELN gene and reduces ELN mRNA production. The product of the ELN gene, the protein ELN or tropoelastin (a subunit of elastin), is a secreted factor that reduces motility. Thus, we propose that a rise in ANKRD1 during early senescence transiently limits the YBOX1-dependent transcriptional increase in ELN production, and thereby enables cell motility in early phases of senescence.

2023-06-01 | MSV000092079 | MassIVE

miR-127-3p is an epigenetic activator of myofibroblast senescence situated within the miRNA enriched Dlk1-Dio3 imprinted domain on mouse chromosome 12 [miRNA array]

Project description:During wound healing, fibroblasts differentiate into non-proliferative contractile myofibroblasts, contribute to skin repair, and eventually undergo apoptosis or become senescent. MicroRNAs (miR) are posttranscriptional regulators of gene expression networks that control cell fate and survival and may also regulate senescence. Here we determined regulated miRs in myofibroblasts isolated from wounds and analyzed their role in senescent myofibroblast formation. Transcriptome profiling showed that a 200 kbp region of the Dlk1-Dio3 imprinted domain on mouse chromosome 12 encodes for most of the upregulated miRs in the entire genome of mouse myofibroblasts. Among those, miR-127-3p induced a myofibroblast-like phenotype associated with a block in proliferation. Molecular analysis revealed that miR-127-3p induced a prolonged cell-cycle arrest with unique molecular features of senescence, including the activation of the senescence-associated ß-galactosidase, increase in p21 levels, inhibition of lamin B1, proliferation factors, and the production of senescence-associated inflammatory and extracellular matrix -remodeling components. Hence, miR-127-3p emerges as an epigenetic activator regulating the transition from repair to remodeling during skin wound healing, but may also induce age-related defects, pathological scarring and fibrosis, all linked to myofibroblast senescence.

2021-01-31 | GSE160921 | GEO

miR-127-3p is an epigenetic activator of myofibroblast senescence situated within the miRNA enriched Dlk1-Dio3 imprinted domain on mouse chromosome 12 [mRNA array]

2021-01-31 | GSE160920 | GEO

Metabolic Reprogramming and Reliance in Human Skin Wound Healing

Project description:Impaired skin wound healing is a significant global health issue, especially among the elderly. Wound healing is a well-orchestrated process involving the sequential phases of inflammation, proliferation, and tissue remodeling. Although wound healing is a highly dynamic and energy-requiring process, the role of metabolism remains largely unexplored. By combining transcriptomics and metabolomics of human skin biopsy samples, we mapped the core bioenergetic and metabolic changes in normal acute as well as chronic wounds in elderly subjects. We found upregulation of glycolysis, the tricarboxylic acid cycle, glutaminolysis, and β-oxidation in the later stages of acute wound healing and in chronic wounds. To ascertain the role of these metabolic pathways on wound healing, we targeted each pathway in a wound healing assay as well as in a human skin explant model using metabolic inhibitors and stimulants. Enhancement or inhibition of glycolysis and, to a lesser extent, glutaminolysis had a far greater impact on wound healing than similar manipulations of oxidative phosphorylation and fatty acid β-oxidation. These findings increase the understanding of wound metabolism and identify glycolysis and glutaminolysis as potential targets for therapeutic intervention.

2024-07-02 | MTBLS3315 | MetaboLights

ANT2 accelerates cutaneous wound healing in aged skin by reverse senescence

Project description:An effective healing response is critical to healthy aging. Thus, the connection of regeneration and aging is needed to understand the complicated age-related healing process. Energy metabolism has been a common hallmark of both studies. In recent years, it become an emerging factor of skin homeostasis. Adenine nucleotide translocase-2 (ANT2) is a known cell proliferation marker and mediator of ATP import into mitochondria for energy homeostasis. Although energy homeostasis and the maintenance of mitochondrial function are critical for wound healing, the role of ANT2 in wound healing has not been elucidated. We found that ANT2 expression decreased during aging in mouse skin as well as during cellular senescence. Interestingly, overexpression of ANT2 in aged mouse skin promoted the healing of full-thickness cutaneous wounds. In addition, upregulation of ANT2 in replicative senescent human diploid dermal fibroblasts (HDFs) induced cell proliferation and migration, which are critical for the wound healing process. Furthermore, overexpression of ANT2 increased ATP production rate by activating the glycolysis pathway and also increased mitophagy, both of which are involved in energy homeostasis. Notably, ANT2-mediated upregulation of HSPA6 in aged HDFs inhibited the expression of pro-inflammatory genes that mediate cellular senescence and mitochondrial damage. This study demonstrates a new physiological role of ANT2 in skin wound healing via regulation of cell proliferation, energy homeostasis, and inflammation. Thus, our study links energy metabolism to skin homeostasis and identifies a genetic factor for improving wound healing with aging model.

2022-11-21 | GSE206141 | GEO

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