RESUMEN
Skin is the largest human organ with easily noticeable biophysical manifestations of aging. As human tissues age, there is chronological accumulation of biophysical changes due to internal and environmental factors. Skin aging leads to decreased elasticity and the loss of dermal matrix integrity via degradation. The mechanical properties of the dermal matrix are maintained by fibroblasts, which undergo replicative aging and may reach senescence. While the secretory phenotype of senescent fibroblasts is well studied, little is known about changes in the fibroblasts biophysical phenotype. Therefore, we compare biophysical properties of young versus proliferatively aged primary fibroblasts via fluorescence and traction force microscopy, single-cell atomic force spectroscopy, microfluidics, and microrheology of the cytoskeleton. Results show senescent fibroblasts have decreased cytoskeletal tension and myosin II regulatory light chain phosphorylation, in addition to significant loss of traction force. The alteration of cellular forces is harmful to extracellular matrix homeostasis, while decreased cytoskeletal tension can amplify epigenetic changes involved in senescence. Further exploration and detection of these mechanical phenomena provide possibilities for previously unexplored pharmaceutical targets against aging.
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Senescencia Celular , Piel , Humanos , Anciano , Senescencia Celular/genética , Células Cultivadas , Envejecimiento , Fibroblastos/metabolismoRESUMEN
Mutations in the CD18 gene encoding the common ß-chain of ß2 integrins result in impaired wound healing in humans and mice suffering from leukocyte adhesion deficiency syndrome type 1 (LAD1). Transplantation of adipose tissue-derived mesenchymal stem cells (MSCs) restores normal healing of CD18-/- wounds by restoring the decreased TGF-ß1 concentrations. TGF-ß1 released from MSCs leads to enhanced myofibroblast differentiation, wound contraction, and vessel formation. We uncover that MSCs are equipped with a sensing mechanism for TGF-ß1 concentrations at wound sites. Low TGF-ß1 concentrations as occurring in CD18-/- wounds induce TGF-ß1 release from MSCs, whereas high TGF-ß1 concentrations suppress TGF-ß1 production. This regulation depends on TGF-ß receptor sensing and is relayed to microRNA-21 (miR-21), which subsequently suppresses the translation of Smad7, the negative regulator of TGF-ß1 signaling. Inactivation of TGF-ß receptor, or overexpression or silencing of miR-21 or Smad7, abrogates TGF-ß1 sensing, and thus prevents the adaptive MSC responses required for tissue repair.
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Síndrome de Deficiencia de Adhesión del Leucocito , Células Madre Mesenquimatosas , Animales , Diferenciación Celular , Ratones , Factor de Crecimiento Transformador beta1/genética , Cicatrización de Heridas/genéticaRESUMEN
We here address the question whether the unique capacity of mesenchymal stem cells to re-establish tissue homeostasis depends on their potential to sense pathogen-associated molecular pattern and, in consequence, mount an adaptive response in the interest of tissue repair. After injection of MSCs primed with the bacterial wall component LPS into murine wounds, an unexpected acceleration of healing occurs, clearly exceeding that of non-primed MSCs. This correlates with a fundamental reprogramming of the transcriptome in LPS-treated MSCs as deduced from RNAseq analysis and its validation. A network of genes mediating the adaptive response through the Toll-like receptor 4 (TLR4) pathway responsible for neutrophil and macrophage recruitment and their activation profoundly contributes to enhanced wound healing. In fact, injection of LPS-primed MSCs silenced for TLR4 fails to accelerate wound healing. These unprecedented findings hold substantial promise to refine current MSC-based therapies for difficult-to-treat wounds.
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Células Madre Mesenquimatosas , Receptor Toll-Like 4 , Animales , Macrófagos , Ratones , Transducción de Señal , Piel , Receptor Toll-Like 4/genética , Cicatrización de Heridas/genéticaRESUMEN
In this study, we report the beneficial effects of a newly identified dermal cell subpopulation expressing the ATP-binding cassette subfamily B member 5 (ABCB5) for the therapy of nonhealing wounds. Local administration of dermal ABCB5+ -derived mesenchymal stem cells (MSCs) attenuated macrophage-dominated inflammation and thereby accelerated healing of full-thickness excisional wounds in the iron-overload mouse model mimicking the nonhealing state of human venous leg ulcers. The observed beneficial effects were due to interleukin-1 receptor antagonist (IL-1RA) secreted by ABCB5+ -derived MSCs, which dampened inflammation and shifted the prevalence of unrestrained proinflammatory M1 macrophages toward repair promoting anti-inflammatory M2 macrophages at the wound site. The beneficial anti-inflammatory effect of IL-1RA released from ABCB5+ -derived MSCs on human wound macrophages was conserved in humanized NOD-scid IL2rγ null mice. In conclusion, human dermal ABCB5+ cells represent a novel, easily accessible, and marker-enriched source of MSCs, which holds substantial promise to successfully treat chronic nonhealing wounds in humans. Stem Cells 2019;37:1057-1074.
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Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Dermis/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Sobrecarga de Hierro/metabolismo , Úlcera de la Pierna/metabolismo , Células Madre Mesenquimatosas/metabolismo , Cicatrización de Heridas , Animales , Línea Celular , Dermis/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Sobrecarga de Hierro/patología , Úlcera de la Pierna/patología , Células Madre Mesenquimatosas/patología , Ratones , Ratones Endogámicos NOD , Ratones SCIDRESUMEN
Increased concentrations of reactive oxygen species (ROS) originating from dysfunctional mitochondria contribute to diverse aging-related degenerative disorders. But so far little is known about the impact of distinct ROS on metabolism and fate of stromal precursor cells. Here, we demonstrate that an increase in superoxide anion radicals due to superoxide dismutase 2 (Sod2) deficiency in stromal precursor cells suppress osteogenic and adipogenic differentiation through fundamental changes in the global metabolite landscape. Our data identify impairment of the pyruvate and l-glutamine metabolism causing toxic accumulation of alpha-ketoglutarate in the Sod2-deficient and intrinsically aged stromal precursor cells as a major cause for their reduced lineage differentiation. Alpha-ketoglutarate accumulation led to enhanced nucleocytoplasmic vacuolation and chromatin condensation-mediated cell death in Sod2-deficient stromal precursor cells as a consequence of DNA damage, Hif-1α instability, and reduced histone H3 (Lys27) acetylation. These findings hold promise for prevention and treatment of mitochondrial disorders commonly associated with aged individuals. Stem Cells 2017;35:1704-1718.
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Envejecimiento/metabolismo , Cromatina/metabolismo , Ácidos Cetoglutáricos/metabolismo , Células Madre Mesenquimatosas/metabolismo , Mitocondrias/metabolismo , Superóxido Dismutasa/genética , Adipocitos/metabolismo , Adipocitos/patología , Envejecimiento/patología , Animales , Animales Recién Nacidos , Muerte Celular , Diferenciación Celular/genética , Condrocitos/metabolismo , Condrocitos/patología , Cromatina/patología , Regulación de la Expresión Génica , Glutamina/metabolismo , Histonas/genética , Histonas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Células Madre Mesenquimatosas/patología , Metaboloma , Ratones , Ratones Noqueados , Mitocondrias/patología , Osteoblastos/metabolismo , Osteoblastos/patología , Cultivo Primario de Células , Ácido Pirúvico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Piel/metabolismo , Piel/patología , Superóxido Dismutasa/deficienciaRESUMEN
Cells and tissues are exposed to stress from numerous sources. Senescence is a protective mechanism that prevents malignant tissue changes and constitutes a fundamental mechanism of aging. It can be accompanied by a senescence associated secretory phenotype (SASP) that causes chronic inflammation. We present a Boolean network model-based gene regulatory network of the SASP, incorporating published gene interaction data. The simulation results describe current biological knowledge. The model predicts different in-silico knockouts that prevent key SASP-mediators, IL-6 and IL-8, from getting activated upon DNA damage. The NF-κB Essential Modulator (NEMO) was the most promising in-silico knockout candidate and we were able to show its importance in the inhibition of IL-6 and IL-8 following DNA-damage in murine dermal fibroblasts in-vitro. We strengthen the speculated regulator function of the NF-κB signaling pathway in the onset and maintenance of the SASP using in-silico and in-vitro approaches. We were able to mechanistically show, that DNA damage mediated SASP triggering of IL-6 and IL-8 is mainly relayed through NF-κB, giving access to possible therapy targets for SASP-accompanied diseases.
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Senescencia Celular/fisiología , Daño del ADN/fisiología , Modelos Biológicos , Transducción de Señal/fisiología , Animales , Células Cultivadas , Biología Computacional , Simulación por Computador , Fibroblastos , Interleucina-6/antagonistas & inhibidores , Interleucina-6/metabolismo , Interleucina-8/antagonistas & inhibidores , Interleucina-8/metabolismo , RatonesRESUMEN
The naked mole-rat (NMR) Heterocephalus glaber (from the Greek/latin words á¼τερος, heteros = divergent, κεφαλή, kephale = head and glabra = hairless) was first described by Rüppell (Fig. 1) and belongs to the Hystricognath (from the Greek words á½στριξ, hystrix = porcupine and γνάθος, gnathos = jaw) as a suborder of rodents. NMR are characterized by the highest longevity among rodents and reveal a profound cancer resistance. Details of its skin-specific protective and resistance mechanisms against aging and carcinogenesis have so far not been adequately characterized. Recently, our knowledge of NMR skin biology was complemented and expanded by published data using state-of-the art histological and molecular techniques. Here we review and integrate novel published data regarding skin morphology and histology of the aging NMR and the underlying mechanisms at the cellular and molecular level. We relate this data to the longevity of the NMR and its resistance to neoplastic transformation and discuss further open questions to understand its extraordinary longevity. In addition, we will address the exposome, defined as "the total of all non-genetic, endogenous and exogenous environmental influences" on the skin, respiratory tract, stomach, and intestine. Finally, we will discuss in perspective further intriguing possibilities arising from the interaction of skin with other organs.
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Neoplasias , Resiliencia Psicológica , Animales , Envejecimiento/patología , Longevidad , Ratas TopoRESUMEN
Cellular senescence is a phenotype characterized by cessation of cell division, which can be caused by exhaustive replication or environmental stress. It is involved in age-related pathophysiological conditions and affects both the cellular cytoskeleton and the prime cellular mechanosensors, focal adhesion complexes. While the size of focal adhesions increases during senescence, it is unknown if and how this is accompanied by a remodeling of the internal focal adhesion structure. Our study uses metal-induced energy transfer to study the axial dimension of focal adhesion proteins from oxidative-stress-induced senescent cells with nanometer precision, and compares these to unstressed cells. We influenced cytoskeletal tension and the functioning of mechanosensitive ion channels using drugs and studied the combined effect of senescence and drug intervention on the focal adhesion structure. We found that H2O2-induced restructuring of the focal adhesion complex indicates a loss of tension and altered talin complexation. Mass spectroscopy-based proteomics confirmed the differential regulation of several cytoskeletal proteins induced by H2O2 treatment.
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Adhesiones Focales , Peróxido de Hidrógeno , Adhesiones Focales/metabolismo , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/metabolismo , Citoesqueleto/metabolismo , Proteínas del Citoesqueleto/metabolismo , Hidrógeno/farmacología , Hidrógeno/metabolismo , Adhesión Celular/genéticaRESUMEN
Severe angiopathy is a major driver for diabetes-associated secondary complications. Knowledge on the underlying mechanisms essential for advanced therapies to attenuate these pathologies is limited. Injection of ABCB5+ stromal precursors at the edge of nonhealing diabetic wounds in a murine db/db model, closely mirroring human type 2 diabetes, profoundly accelerates wound closure. Strikingly, enhanced angiogenesis was substantially enforced by the release of the ribonuclease angiogenin from ABCB5+ stromal precursors. This compensates for the profoundly reduced angiogenin expression in nontreated murine chronic diabetic wounds. Silencing of angiogenin in ABCB5+ stromal precursors before injection significantly reduced angiogenesis and delayed wound closure in diabetic db/db mice, implying an unprecedented key role for angiogenin in tissue regeneration in diabetes. These data hold significant promise for further refining stromal precursors-based therapies of nonhealing diabetic foot ulcers and other pathologies with impaired angiogenesis.
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Diabetes Mellitus Tipo 2 , Pie Diabético , Animales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Pie Diabético/patología , Pie Diabético/terapia , Ratones , Ratones Endogámicos , Neovascularización Patológica/patología , Ribonucleasa Pancreática , Cicatrización de HeridasRESUMEN
Human multipotent mesenchymal stromal cells (hMSCs) are currently developed as cell therapeutics for different applications, including regenerative medicine, immune modulation, and cancer treatment. The biological properties of hMSCs can be further modulated by genetic engineering. Viral vectors based on human adenovirus type 5 (HAdV-5) belong to the most frequently used vector types for genetic modification of human cells in vitro and in vivo. However, due to a lack of the primary attachment receptor coxsackievirus and adenovirus receptor (CAR) in hMSCs, HAdV-5 vectors are currently not suitable for transduction of this cell type without capsid modification. Here we present several transduction enhancers that strongly enhance HAdV-5-mediated gene transfer into both bone marrow- and adipose tissue-derived hMSCs. Polybrene, poly-l-lysine, human lactoferrin, human blood coagulation factor X, spermine, and spermidine enabled high eGFP expression levels in hMSCs. Importantly, hMSCs treated with enhancers were not affected in their migration behavior, which is a key requisite for many therapeutic applications. Exemplary, strongly increased expression of tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6) (a secreted model therapeutic protein) was achieved by enhancer-facilitated HAdV-5 transduction. Thus, enhancer-mediated HAdV-5 vector transduction is a valuable method for the engineering of hMSCs, which can be further exploited for the development of innovative hMSC therapeutics.
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Adenovirus Humanos/genética , Vectores Genéticos , Células Madre Mesenquimatosas/virología , Transducción Genética/métodos , Diferenciación Celular , Células Cultivadas , Técnicas de Cocultivo , Terapia Genética/métodos , Humanos , Macrófagos/fisiologíaRESUMEN
Fibroblasts residing in the connective tissues constitute the stem cell niche, particularly in organs such as skin. Although the effect of fibroblasts on stem cell niches and organ aging is an emerging concept, the underlying mechanisms are largely unresolved. We report a mechanism of redox-dependent activation of transcription factor JunB, which, through concomitant upregulation of p16INK4A and repression of insulin growth factor-1 (IGF-1), initiates the installment of fibroblast senescence. Fibroblast senescence profoundly disrupts the metabolic and structural niche, and its essential interactions with different stem cells thus enforces depletion of stem cells pools and skin tissue decline. In fact, silencing of JunB in a fibroblast-niche-specific manner-by reinstatement of IGF-1 and p16 levels-restores skin stem cell pools and overall skin tissue integrity. Here, we report a role of JunB in the control of connective tissue niche and identified targets to combat skin aging and associated pathologies.
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Comunicación Celular , Fibroblastos/metabolismo , Envejecimiento de la Piel , Piel/metabolismo , Nicho de Células Madre , Células Madre/metabolismo , Factores de Transcripción/metabolismo , Animales , Células Cultivadas , Senescencia Celular , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Ratones Noqueados , Piel/patología , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxidos/metabolismo , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: The occurrence of chronic wounds, account for significant suffering of diabetic people, together with increasing healthcare burden. The chronic wounds associated with diabetes do not undergo the normal healing process rather stagnate into chronic proinflammatory phase as well as declined fibroblast function and impaired cell migration. HYPOTHESIS: SIRT1, which is the most studied isoform of the sirtuin family in mammals, has now emerged as a crucial target for improving diabetic wound healing. It is an NAD+ dependent deacetylase, originally characterized to deacetylate histone proteins leading to heterochromatin formation and gene silencing. It is now known to regulate a number of cellular processes like cell proliferation, division, senescence, apoptosis, DNA repair, and metabolism. METHODOLOGY: The retrieval of potentially relevant studies was done by systematically searching of three databases (Google Scholar, Web of science and PubMed) in December 2019. The keywords used as search terms were related to SIRT1 and wound healing. The systematic search retrieved 649 papers that were potentially relevant and after selection procedure, 73 studies were included this review and discussed below. RESULTS: Many SIRT1 activating compounds (SACs) were found protective and improve diabetic wound healing through regulation of inflammation, cell migration, oxidative stress response and formation of granulation tissue at the wound site. CONCLUSIONS: However, contradictory reports describe the opposing role of SACs on the regulation of cell migration and cancer incidence. SACs are therefore subjected to intense research for understanding the mechanisms responsible for controlling cell migration and therefore possess prospective to enter the clinical arena in the foreseeable future.
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Chronic wounds pose a stern challenge to health care systems with growing incidence especially in the aged population. In the presence of increased iron concentrations, recruitment of monocytes from the circulation and activation towards ROS and RNS releasing M1 macrophages together with the persistence of senescent fibroblasts at the wound site are significantly enhanced. This unrestrained activation of pro-inflammatory macrophages and senescent fibroblasts has increasingly been acknowledged as main driver causing non-healing wounds. In a metaphor, macrophages act like stage directors of wound healing, resident fibroblasts constitute main actors and increased iron concentrations are decisive parts of the libretto, and - if dysregulated - are responsible for the development of non-healing wounds. This review will focus on recent cellular and molecular findings from chronic venous leg ulcers and diabetic non-healing wounds both constituting the most common pathologies often resulting in limb amputations of patients. This not only causes tremendous suffering and loss of life quality, but is also associated with an increase in mortality and a major socio-economic burden. Despite recent advances, the underlying molecular mechanisms are not completely understood. Overwhelming evidence shows that reactive oxygen species and the transition metal and trace element iron at pathological concentrations are crucially involved in a complex interplay between cells of different histogenetic origin and their extracellular niche environment. This interplay depends on a variety of cellular, non-cellular biochemical and cell biological mechanisms. Here, we will highlight recent progress in the field of iron-dependent regulation of macrophages and fibroblasts and related pathologies linked to non-healing chronic wounds.
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Hierro/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cicatrización de Heridas , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Macrófagos/metabolismo , Macrófagos/patologíaRESUMEN
We here investigated whether the unique capacity of mesenchymal stem cells (MSCs) to re-establish tissue homeostasis depends on their potential to sense danger associated molecular pattern (DAMP) and to mount an adaptive response in the interest of tissue repair. Unexpectedly, after injection of MSCs which had been pretreated with the calcium-binding DAMP protein S100A8/A9 into murine full-thickness wounds, we observed a significant acceleration of healing even exceeding that of non-treated MSCs. This correlates with a fundamental reprogramming of the transcriptome in S100A8/A9 treated MSCs as deduced from RNA-seq analysis and its validation. A network of genes involved in proteolysis, macrophage phagocytosis, and inflammation control profoundly contribute to the clean-up of the wound site. In parallel, miR582-5p and genes boosting energy and encoding specific extracellular matrix proteins are reminiscent of scar-reduced tissue repair. This unprecedented finding holds substantial promise to refine current MSC-based therapies for difficult-to-treat wounds and fibrotic conditions.
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A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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Transcription factors ensure skin homeostasis via tight regulation of distinct resident stem cells. Here we report that JunB, a member of the AP-1 transcription factor family, regulates epidermal stem cells and sebaceous glands through balancing proliferation and differentiation of progenitors and by suppressing lineage infidelity. JunB deficiency in basal progenitors results in a dermatitis-like syndrome resembling seborrheic dermatitis harboring structurally and functionally impaired sebaceous glands with a globally altered lipid profile. A fate switch occurs in a subset of JunB deficient epidermal progenitors during wound healing resulting in de novo formation of sebaceous glands. Dysregulated Notch signaling is identified to be causal for this phenotype. In fact, pharmacological inhibition of Notch signaling can efficiently restore the lineage drift, impaired epidermal differentiation and disrupted barrier function in JunB conditional knockout mice. These findings define an unprecedented role for JunB in epidermal-pilosebaceous stem cell homeostasis and its pathology.
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Transducción de Señal/fisiología , Factores de Transcripción/metabolismo , Animales , Diferenciación Celular/fisiología , Epidermis/metabolismo , Ratones , Ratones Noqueados , Glándulas Sebáceas/citología , Glándulas Sebáceas/metabolismo , Células Madre/citología , Células Madre/metabolismo , Factores de Transcripción/genética , Cicatrización de Heridas/genética , Cicatrización de Heridas/fisiologíaRESUMEN
Being a powerful tool in modelling industrial and service operations, Petri net (PN) has been extremely used in different domains, but its application in safety study is limited. In this study, we model the gantry crane operations used for industrial activities using generalized stochastic PNs. The complete cycle of operations of the gantry crane is split into three parts namely inspection and loading, movement of load, and unloading of load. PN models are developed for all three parts and the whole system as well. The developed PN models have captured the safety issues through reachability tree. The hazardous states are identified and how they ultimately lead to some unwanted accidents is demonstrated. The possibility of falling of load and failure of hook, sling, attachment and hoist rope are identified. Possible suggestions based on the study are presented for redesign of the system. For example, mechanical stoppage of operations in case of loosely connected load, and warning system for use of wrong buttons is tested using modified models.
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Industria de la Construcción , Salud Laboral , Industria de la Construcción/métodos , Humanos , Modelos TeóricosRESUMEN
PGC-1α is a versatile inducer of mitochondrial biogenesis and responsive to the changing energy demands of the cell. As mitochondrial ATP production requires proteins that derive from translation products of cytosolic ribosomes, we asked whether PGC-1α directly takes part in ribosomal biogenesis. Here, we show that a fraction of cellular PGC-1α localizes to the nucleolus, the site of ribosomal transcription by RNA polymerase I. Upon activation PGC-1α associates with the ribosomal DNA and boosts recruitment of RNA polymerase I and UBF to the rDNA promoter. This induces RNA polymerase I transcription under different stress conditions in cell culture and mouse models as well as in healthy humans and is impaired already in early stages of human Huntington's disease. This novel molecular link between ribosomal and mitochondrial biogenesis helps to explain sarcopenia and cachexia in diseases of neurodegenerative origin.
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Enfermedad de Huntington/patología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , ARN Ribosómico/biosíntesis , Transcripción Genética , Adulto , Anciano , Animales , Biopsia , Células Cultivadas , ADN/metabolismo , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Mitocondrias/metabolismo , Biogénesis de Organelos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Proteínas del Complejo de Iniciación de Transcripción Pol1/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , ARN Polimerasa I/metabolismo , Adulto JovenRESUMEN
The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions (O2â-) in mitochondria, either by chemical inhibition of complex I or by genetic silencing of O2â--dismutating mitochondrial Sod2. The O2â--dependent suppression of IGF-1 signalling resulted in decreased proliferation of murine dermal fibroblasts, affected translation initiation factors and suppressed the expression of α1(I), α1(III), and α2(I) collagen, the hallmarks of skin ageing. Enhanced O2â- led to activation of the phosphatases PTP1B and PTEN, which via dephosphorylation of the IGF-1 receptor and phosphatidylinositol 3,4,5-triphosphate dampened IGF-1 signalling. Genetic and pharmacologic inhibition of PTP1B and PTEN abrogated O2â--induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with O2â-, PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies.
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Envejecimiento/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Fosfohidrolasa PTEN/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Superóxidos/metabolismo , Envejecimiento/genética , Animales , Humanos , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Fosfohidrolasa PTEN/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 1/genética , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Transducción de Señal , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismoRESUMEN
The free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. The skin represents an excellent and accessible model organ to study aging that is characterized by atrophy, wrinkle formation, reduced tensile strength and impaired wound healing. Oxidative stress as a consequence of an imbalance in prooxidants and antioxidants with increased ROS concentrations has been demonstrated in the aged skin in vitro and in vivo, suggesting the important role of the antioxidant balance. Here we will summarize recent data on the role of the mitochondrial superoxide dismutase 2 in skin aging.