Cellular senescence is a fundamental stress response that restrains tumour formation. Yet, senescence cells are also present in non-cancerous states, accumulating exponentially with chronological age and contributing to age- and diabetes-related cellular dysfunction. The identification of hypersecretory and phagocytic behaviours in cells that were once believed to be non-functional has led to a recent explosion of senescence research. Here we discuss the profound, and often opposing, roles identified for short-lived vs. chronic tissue senescence. Transiently induced senescence is required for development, regeneration and acute wound repair, while chronic senescence is widely implicated in tissue pathology. We recently demonstrated that sustained senescence contributes to impaired diabetic healing via the CXCR2 receptor, which when blocked promotes repair. Further studies have highlighted the beneficial effects of targeting a range of senescence-linked processes to fight disease. Collectively, these findings hold promise for developing clinically viable strategies to tackle senescence in chronic wounds and other cutaneous pathologies.
Last. Satomi Miwa(Newcastle University)H-Index: 28
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SIGNIFICANCE: Cell senescence was originally defined by an acute loss of replicative capacity and thus thought to be restricted to proliferation-competent cells. More recently, senescence has been recognised as a cellular stress and damage response encompassing multiple pathways or senescence domains, namely DNA Damage Response (DDR), cell cycle arrest, Senescence-Associated Secretory Phenotype (SASP), Senescence-Associated Mitochondrial Dysfunction (SAMD), Autophagy/Mitophagy Dysfunction, Nutri...
Arguably, the two most important causes of pathological healing in the skin are diabetes and ageing. While these factors have historically been considered independent modifiers of the healing process, recent studies suggest that they may be mechanistically linked. The primary contributor to diabetic pathology is hyperglycaemia, which accelerates the production of advanced glycation end products, a characteristic of ageing tissue. Indeed, advanced age also leads to mild hyperglycaemia. Here, we d...
Cellular senescence is a tumor-suppressive mechanism blocking cell proliferation in response to stress. However, recent evidence suggests that senescent tumor cells can re-enter the cell cycle to become cancer stem cells, leading to relapse after cancer chemotherapy treatment. Understanding how the senescence reprogramming process is a precursor to cancer stem cell formation is of great medical importance. To study the interplay between senescence, stemness, and cancer, we applied a stem cell me...
Cellular senescence is a stress response that limits the proliferation of damaged cells by establishing a permanent cell cycle arrest. Different stimuli can trigger senescence but excessive production or impaired clearance of these cells can lead to their accumulation during aging with deleterious effects. Despite this potential negative side of cell senescence, its physiological role as a pro-regenerative and morphogenetic force has emerged recently after the identification of programmed cell s...
#1Cayetano von Kobbe(CSIC: Spanish National Research Council)H-Index: 26
Cellular senescence is a hallmark of aging, whose onset is linked to a series of both cell and non-cell autonomous processes, leading to several consequences for the organism. To date, several senescence routes have been identified, which play a fundamental role in development, tumor suppression and aging, among other processes. The positive and/or negative effects of senescent cells are directly related to the time that they remain in the organism. Short-term (acute) senescent cells are associa...
Aging is a pleiotropic process affecting many aspects of mammalian physiology. Mammals are composed of distinct cell type identities and tissue environments, but the influence of these cell identities and environments on the trajectory of aging in individual cells remains unclear. Here, we performed single-cell RNA-seq on >50,000 individual cells across three tissues in young and old mice to allow for direct comparison of aging phenotypes across cell types. We found transcriptional features of a...
In chemotherapy-treated breast cancer, wild-type p53 preferentially induces senescence over apoptosis, resulting in a persisting cell population constituting residual disease that drives relapse and poor patient survival via the senescence-associated secretory phenotype. Understanding the properties of tumor cells that allow survival after chemotherapy treatment is paramount. Using time-lapse and confocal microscopy to observe interactions of cells in treated tumors, we show here that chemothera...
Iron is crucial for maintaining normal bodily function with well-documented roles in erythropoiesis, hemostasis, and inflammation. Despite this, little is known about the temporal regulation of iron during wound healing, or how iron contributes to wound biology and pathology. In this study, we profiled tissue iron levels across a healing time-course, identifying iron accumulation during late-stage repair. Diabetic murine wounds displayed significantly reduced iron levels, delayed extracellular m...
Abstract Cellular senescence was traditionally considered a stress response that protected the organism by limiting the proliferation of damaged and unwanted cells. However, the recent identification of developmentally-programmed cellular senescence during embryo development has changed our view of the process. There are now a number of examples of developmental senescence in evolutionary distant organisms ranging from mammals to fish, showing senescence at various sites during specific time win...
ABSTRACT Cellular senescence is a state comprising an essentially irreversible proliferative arrest combined with phenotypic changes and pronounced secretory activity. Although senescence has long been linked with aging, recent studies have uncovered functional roles for senescence in embryonic development, regeneration and reprogramming, and have helped to advance our understanding of this process as a highly coordinated and programmed cellular state. In this Primer article, we summarize some o...
Senescent cells have detrimental effects across tissues with aging but may have beneficial effects on tissue repair, specifically on skin wound healing. However, the potential role of senescent cells in fracture healing has not been defined. Here, we performed an in silico analysis of public mRNAseq data and found that senescence and senescence-associated secretory phenotype (SASP) markers increased during fracture healing. We next directly established that the expression of senescence biomarker...
Aging increases the susceptibility to a diverse set of diseases and disorders, including neurodegeneration, cancer, diabetes, and arthritis. Natural compounds are currently being explored as alternative or complementary agents to treat or prevent aging-related malfunctions. Curcumin, a phytochemical isolated from the spice turmeric, has garnered great interest in recent years. With anti-oxidant, anti-inflammatory, anti-microbial, and other physiological activities, curcumin has great potential f...
Plants are rich sources of a diverse range of chemicals, many of which have significant metabolic activity. One large group of secondary compounds are the phenolics, which act as inter alia potent reactive oxygen scavengers in cells, including fibroblasts. These common dermis residue cells play a crucial role in the production of extracellular matrix components, such as collagen, and maintaining the integrity of connective tissue. Chronic wounds or skin exposure to UV-irradiation disrupt fibrobl...
Dermal fibroblasts are the main actor in many proteins’ secretion, including collagen, preserving skin function. Free radicals are involved in skin aging and damages involving different cellular components. The imbalance between reactive oxygen species (ROS) amount and natural antioxidant enzymes negatively affects skin homeostasis. Natural compounds have recently emerged as a potential anti-aging tool in tissue regeneration. In the present paper we evaluated the antioxidant activity of white an...
Wound healing is a complex process, and disturbance of even a single mechanism can result in chronic ulcers developing after exposure to the alkylating agent sulfur mustard (SM). A possible contributor may be SM-induced chronic senescent mesenchymal stem cells (MSCs), unable to fulfil their regenerative role, by persisting over long time periods and creating a proinflammatory microenvironment. Here we show that senescence induction in human bone marrow derived MSCs was time- and concentration-de...
Venous leg ulcers (VLU) represent an uphill economic, health and social burden, aggravated in the elderly. Best-practice care interventions are often insufficient and alternative therapies need to be explored. Herein, we have treated for the first time a chronic VLU in an elderly patient by combining cell therapy and tissue engineering in the context of a compassionate use. The administration of allogeneic adipose-derived mesenchymal stromal cells (MSCs) embedded in a plasma-based bioengineered ...