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The word "secretome" was first used to describe the proteins that cells secrete under different circumstances; however, recent studies have proven the existence of other molecules such as RNA and chemical compounds in the secretome. The study of secretome has significance for the diagnosis and treatment of disease as it provides insight into cellular functions, including immune responses, development, and homeostasis. By halting cell division, cellular senescence plays a role in both cancer defense and aging by secreting substances known as senescence-associated secretory phenotypes (SASP). A variety of techniques could be used to analyze the secretome: protein-based approaches like mass spectrometry and protein microarrays, nucleic acid-based methods like RNA sequencing, microarrays, and in silico prediction. Each method offers unique advantages and limitations in characterizing secreted molecules. Top-down and bottom-up strategies for thorough secretome analysis are became possible by mass spectrometry. Understanding cellular function, disease causes, and proper treatment targets is aided by these methodologies. Their approaches, benefits, and drawbacks will all be discussed in this review.
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The battle against the COVID-19 pandemic has spurred a heightened state of vigilance in global healthcare, leading to the proliferation of diverse sanitization methods. Among these approaches, germicidal lamps utilizing ultraviolet (UV) rays, particularly UV-C (wavelength ranging from 280 to 100 nm), have gained prominence for domestic use. These light-emitting diode (LED) lamps are designed to sanitize the air, objects, and surfaces. However, the prevailing concern is that these UV lamps are often introduced into the market without adequate accompanying information to ensure their safe utilization. Importantly, exposure to absorbed UV light can potentially trigger adverse biological responses, encompassing cell death and senescence. Our research encompassed a series of investigations aimed at comprehending the biological repercussions of UV-C radiation exposure from readily available domestic lamps. Our focus centered on epithelial retinal cells, keratinocytes, and fibroblasts, components of the skin and ocular targets frequently exposed to UV irradiation. Our findings underscore the potential harm associated with even brief exposure to UV, leading to irreversible and detrimental alterations in both skin cells and retinal cells of the eye. Notably, epithelial retinal cells exhibited heightened sensitivity, marked by substantial apoptosis. In contrast, keratinocytes demonstrated resilience to apoptosis even at elevated UV doses, though they were prone to senescence. Meanwhile, fibroblasts displayed a gradual amplification of both senescence and apoptosis as radiation doses escalated. In summary, despite the potential benefits offered by UV-C in deactivating pathogens like SARS-CoV-2, it remains evident that the concurrent risks posed by UV-C to human health cannot be ignored.
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Apoptosis , COVID-19 , Senescencia Celular , SARS-CoV-2 , Rayos Ultravioleta , Rayos Ultravioleta/efectos adversos , Apoptosis/efectos de la radiación , Humanos , Senescencia Celular/efectos de la radiación , SARS-CoV-2/efectos de la radiación , Queratinocitos/efectos de la radiación , Fibroblastos/efectos de la radiaciónRESUMEN
Mammals exhibit two distinct types of adipose depots: white adipose tissue (WAT) and brown adipose tissue (BAT). While WAT primarily functions as a site for energy storage, BAT serves as a thermogenic tissue that utilizes energy and glucose consumption to regulate core body temperature. Under specific stimuli such as exercise, cold exposure, and drug treatment, white adipocytes possess a remarkable ability to undergo transdifferentiation into brown-like cells known as beige adipocytes. This transformation process, known as the "browning of WAT," leads to the acquisition of new morphological and physiological characteristics by white adipocytes. We investigated the potential role of Irisin, a 12 kDa myokine that is secreted in mice and humans by skeletal muscle after physical activity, in inducing the browning process in mesenchymal stromal cells (MSCs). A subset of the MSCs possesses the remarkable capability to differentiate into different cell types such as adipocytes, osteocytes, and chondrocytes. Consequently, comprehending the effects of Irisin on MSC biology becomes a crucial factor in investigating antiobesity medications. In our study, the primary objective is to evaluate the impact of Irisin on various cell types engaged in distinct stages of the differentiation process, including stem cells, committed precursors, and preadipocytes. By analyzing the effects of Irisin on these specific cell populations, our aim is to gain a comprehensive understanding of its influence throughout the entire differentiation process, rather than solely concentrating on the final differentiated cells. This approach enables us to obtain insights into the broader effects of Irisin on the cellular dynamics and mechanisms involved in adipogenesis.
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Adipogénesis , Diferenciación Celular , Fibronectinas , Células Madre Mesenquimatosas , Humanos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Fibronectinas/metabolismo , Fibronectinas/farmacología , Diferenciación Celular/efectos de los fármacos , Células CultivadasRESUMEN
Cells that are exposed to harmful genetic damage, either from internal or external sources, may undergo senescence if they are unable to repair their DNA. Senescence, characterized by a state of irreversible growth arrest, can spread to neighboring cells through a process known as the senescence-associated secretory phenotype (SASP). This phenomenon contributes to both aging and the development of cancer. The SASP comprises a variety of factors that regulate numerous functions, including the induction of secondary senescence, modulation of immune system activity, remodeling of the extracellular matrix, alteration of tissue structure, and promotion of cancer progression. Identifying key factors within the SASP is crucial for understanding the underlying mechanisms of senescence and developing effective strategies to counteract cellular senescence. Our research has specifically focused on investigating the role of IGFBP5, a component of the SASP observed in various experimental models and conditions.Through our studies, we have demonstrated that IGFBP5 actively contributes to promoting senescence and can induce senescence in neighboring cells. We have gained valuable insights into the mechanisms through which IGFBP5 exerts its pro-senescence effects. These mechanisms include its release following genotoxic stress, involvement in signaling pathways mediated by reactive oxygen species and prostaglandins, internalization via specialized structures called caveolae, and interaction with a specific protein known as RARα. By uncovering these mechanisms, we have advanced our understanding of the intricate role of IGFBP5 in the senescence process. The significance of IGFBP5 as a pro-aging factor stems from an in vivo study we conducted on patients undergoing Computer Tomography analysis. In these patients, we observed an elevation in circulating IGFBP5 levels in response to radiation-induced organismal stress.Globally, our findings highlight the potential of IGFBP5 as a promising therapeutic target for age-related diseases and cancer.
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Senescencia Celular , Neoplasias , Humanos , Envejecimiento , Células Cultivadas , Senescencia Celular/genética , Neoplasias/metabolismo , Transducción de Señal/genéticaRESUMEN
DNA damage resulting from genotoxic injury can initiate cellular senescence, a state characterized by alterations in cellular metabolism, lysosomal activity, and the secretion of factors collectively known as the senescence-associated secretory phenotype (SASP). Senescence can have beneficial effects on our bodies, such as anti-cancer properties, wound healing, and tissue development, which are attributed to the SASP produced by senescent cells in their intermediate stages. However, senescence can also promote cancer and aging, primarily due to the pro-inflammatory activity of SASP.Studying senescence is complex due to various factors involved. Genotoxic stimuli cause random damage to cellular macromolecules, leading to variations in the senescent phenotype from cell to cell, despite a shared program. Furthermore, senescence is a dynamic process that cannot be analyzed as a static endpoint, adding further complexity.Investigating SASP is particularly intriguing as it reveals how a senescence process triggered in a few cells can spread to many others, resulting in either positive or negative consequences for health. In our study, we conducted a meta-analysis of the protein content of SASP obtained from different research groups, including our own. We categorized the collected omic data based on: i) cell type, ii) harmful agent, and iii) senescence stage (early and late senescence).By employing Gene Ontology and Network analysis on the omic data, we identified common and specific features of different senescent phenotypes. This research has the potential to pave the way for the development of new senotherapeutic drugs aimed at combating the negative consequences associated with the senescence process. Video Abstract.
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Neoplasias , Senoterapéuticos , Humanos , Secretoma , Envejecimiento , Senescencia Celular , Neoplasias/metabolismo , FenotipoRESUMEN
Although adult stem cells may be useful for studying tissue-specific diseases, they cannot be used as a general model for investigating human illnesses given their limited differentiation potential. Multilineage-differentiating stress-enduring (Muse) stem cells, a SSEA3(+) cell population isolated from mesenchymal stromal cells, fat, and skin fibroblasts, may be able to overcome that restriction. The Muse cells present in fibroblast cultures obtained from biopsies of patients' skin may be differentiated into cells of interest for analyzing diseases. We isolated Muse stem cells from patients with an intellectual disability (ID) and mutations in the IQSEC2 gene (i.e., BRAG1 gene) and induced in vitro neuroglial differentiation to study cell commitment and the differentiation of neural lineages. The neuroglial differentiation of Muse cells revealed that IQSEC2 mutations may alter the self-renewal and lineage specification of stem cells. We observed a decrease in the percentage of SOX2 (+) neural stem cells and neural progenitors (i.e., SOX2+ and NESTIN+) in cultures obtained from Muse cells with the mutated IQSEC2 gene. The alteration in the number of stem cells and progenitors produced a bias toward the astrocytes' differentiation. Our research demonstrates that Muse stem cells may represent a new cell-based disease model.
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Diferenciación Celular , Células Madre Mesenquimatosas , Neuroglía , Humanos , Fibroblastos , Factores de Intercambio de Guanina NucleótidoRESUMEN
Genotoxic injuries converge on senescence-executive program that promotes production of a senescence-specific secretome (SASP). The study of SASP is particularly intriguing, since through it a senescence process, triggered in a few cells, can spread to many other cells and produce either beneficial or negative consequences for health. We analysed the SASP of quiescent mesenchymal stromal cells (MSCs) following stress induced premature senescence (SIPS) by ionizing radiation exposure. We performed a proteome analysis of SASP content obtained from early and late senescent cells. The bioinformatics studies evidenced that early and late SASPs, besides some common ontologies and signalling pathways, contain specific factors. In spite of these differences, we evidenced that SASPs can block in vitro proliferation of cancer cells and promote senescence/apoptosis. It is possible to imagine that SASP always contains core components that have an anti-tumour activity, the progression from early to late senescence enriches the SASP of factors that may promote SASP tumorigenic activity only by interacting and instructing cells of the immune system. Our results on Caco-2 cancer cells incubated with late SASP in presence of peripheral white blood cells strongly support this hypothesis. We evidenced that quiescent MSCs following SIPS produced SASP that, while progressively changed its composition, preserved the capacity to block cancer growth by inducing senescence and/or apoptosis only in an autonomous manner.
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Células Madre Mesenquimatosas , Secretoma , Humanos , Células CACO-2 , Senescencia Celular , Carcinogénesis/metabolismo , Células Madre Mesenquimatosas/metabolismoRESUMEN
OBJECTIVES: Multilineage differentiating Stress Enduring (MUSE) cells are endogenous, stress-resistant stem cells, expressing pluripotency master genes and able to differentiate in cells of the three embryonic sheets. Stage-Specific Embryonic Antigen 3 (SSEA-3), a glycosphingolipid (GSL), is the marker for identifying MUSE cells and is used to isolate this population from mesenchymal stromal cells. GSLs modulate signal transduction by interacting with plasma membrane components. The growth factor FGF2, important for MUSE cells biology, may interact with GSLs. Specific cell surface markers represent an invaluable tool for stem cell isolation. Nonetheless their role, if any, in stem cell biology is poorly investigated. Functions of stem cells, however, depend on niche external cues, which reach cells through surface markers. We addressed the role of SSEA-3 in MUSE cell behaviour, trying to define whether SSEA-3 is just a marker or if it plays a functional role in this cell population by determining if it has any relationship with FGF2 activity. RESULTS: We evidenced how the SSEA-3 and FGF2 cooperation affected the self-renewal and clonogenic capacity of MUSE cells. The block of SSEA-3 significantly reduced the multilineage potential of MUSE cells with production of nullipotent clones. CONCLUSIONS: We contributed to dissecting the mechanisms underlying MUSE cell properties for establishing successful stem-cell-based therapies and the promotion of MUSE cells as a tool for the in vitro disease model.
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Alprostadil , Factor 2 de Crecimiento de Fibroblastos , Diferenciación Celular , Antígenos Embrionarios Específico de Estadio/metabolismoRESUMEN
Two different types of adipose depots can be observed in mammals: white adipose tissue (WAT) and brown adipose tissue (BAT). The primary role of WAT is to deposit surplus energy in the form of triglycerides, along with many metabolic and hormonal activities; as thermogenic tissue, BAT has the distinct characteristic of using energy and glucose consumption as a strategy to maintain the core body temperature. Under specific stimuli-such as exercise, cold exposure, and drug treatment-white adipocytes can utilize their extraordinary flexibility to transdifferentiate into brown-like cells, called beige adipocytes, thereby acquiring new morphological and physiological characteristics. For this reason, the process is identified as the 'browning of WAT'. We evaluated the ability of some drugs, including GW501516, sildenafil, and rosiglitazone, to induce the browning process of adult white adipocytes obtained from differentiated mesenchymal stromal cells (MSCs). In addition, we broadened our investigation by evaluating the potential browning capacity of IRISIN, a myokine that is stimulated by muscular exercises. Our data indicate that IRISIN was effective in promoting the browning of white adipocytes, which acquire increased expression of UCP1, increased mitochondrial mass, and modification in metabolism, as suggested by an increase of mitochondrial oxygen consumption, primarily in presence of glucose as a nutrient. These promising browning agents represent an appealing focus in the therapeutic approaches to counteracting metabolic diseases and their associated obesity.
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Adipocitos Blancos , Células Madre Mesenquimatosas , Animales , Adipocitos Blancos/metabolismo , Fibronectinas/metabolismo , Rosiglitazona/farmacología , Citrato de Sildenafil/farmacología , Médula Ósea/metabolismo , Metabolismo Energético , Termogénesis , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Células Madre Mesenquimatosas/metabolismo , Glucosa/metabolismo , Triglicéridos/metabolismo , Mamíferos/metabolismoRESUMEN
Humans are exposed to environmental microplastic (MPs) that can be frequent in surrounding environment. The mesenchymal stromal cells are a heterogeneous population, which contain fibroblasts and stromal cells, progenitor cells and stem cells. They are part of the stromal component of most tissue and organs in our organisms. Any injury to their functions may impair tissue renewal and homeostasis. We evaluated the effects of different size MPs that could be present in water bottles on human bone marrow mesenchymal stromal cells (BMMSCs) and adipose mesenchymal stromal cells (AMSCs). MPs of polyethylene terephthalate (MPs-PET) (<1 µm and <2.6 µm) were tested in this study. PET treatments induced a reduction in proliferating cells (around 30%) associated either with the onset of senescence or increase in apoptosis. The AMSCs and BMMSCs exposed to PET showed an alteration of differentiation potential. AMSCs remained in an early stage of adipocyte differentiation as shown by high levels of mRNA for Peroxisome Proliferator Activated Receptor Gamma (PPARG) (7.51 vs 1.00) and reduction in Lipoprotein Lipase (LPL) mRNA levels (0.5 vs 1.0). A loss of differentiation capacity was also observed for the osteocyte phenotype in BMMSCs. In particular, we observed a reduction in Bone Gamma-Carboxy glutamate Protein (BGLAP) (0.4 for PET1 and 0.6 for PET2.6 vs 0.1 CTRL) and reduction in Osteopontin (SPP1) (0.3 for PET 1 and 0.64 for PET 2.6 vs 0.1 CTRL). This pioneering mesenchymal cell response study demonstrated that environmental microplastic could be bioavailable for cell uptake and may further lead to irreversible diseases.
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Células Madre Mesenquimatosas , Plásticos , Diferenciación Celular , Células Cultivadas , Humanos , Células Madre Mesenquimatosas/metabolismo , Microplásticos/toxicidad , Plásticos/metabolismo , Plásticos/toxicidad , ARN Mensajero/metabolismoRESUMEN
Mesenchymal stromal cells (MSCs), present in the stromal component of several tissues, include multipotent stem cells, progenitors, and differentiated cells. MSCs have quickly attracted considerable attention in the clinical field for their regenerative properties and their ability to promote tissue homeostasis following injury. In recent years, MSCs mainly isolated from bone marrow, adipose tissue, and umbilical cord-have been utilized in hundreds of clinical trials for the treatment of various diseases. However, in addition to some successes, MSC-based therapies have experienced several failures. The number of new trials with MSCs is exponentially growing; still, complete results are only available for a limited number of trials. This dearth does not help prevent potentially inefficacious and unnecessary clinical trials. Results from unsuccessful studies may be useful in planning new therapeutic approaches to improve clinical outcomes. In order to bolster critical analysis of trial results, we reviewed the state of art of MSC clinical trials that have been published in the last six years. Most of the 416 published trials evaluated MSCs' effectiveness in treating cardiovascular diseases, GvHD, and brain and neurological disorders, although some trials sought to treat immune system diseases and wounds and to restore tissue. We also report some unorthodox clinical trials that include unusual studies.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Diferenciación Celular , Trasplante de Células Madre Mesenquimatosas/métodos , Cordón UmbilicalRESUMEN
Several investigations on senescence and its causative role in aging have underscored the importance of developing senotherapeutics, a field focused on killing senescent cells and/or preventing their accumulation within tissues. Using polyphenols in counteracting senescence may facilitate the development of senotherapeutics given their presence in the human diet, their confirmed tolerability and absence of severe side effects, and their role in preventing senescence and inducing the death of senescent cells. Against that background, we evaluated the effect of piceatannol, a natural polyphenol, on the senescence of mesenchymal stromal cells (MSCs), which play a key role in the body's homeostasis. Among our results, piceatannol reduced the number of senescent cells both after genotoxic stress that induced acute senescence and in senescent replicative cultures. Such senotherapeutics activity, moreover, promoted the recovery of cell proliferation and the stemness properties of MSCs. Altogether, our findings demonstrate piceatannol's effectiveness in counteracting senescence by targeting its associated pathways and detecting and affecting P53-dependent and P53-independent senescence. Our study thus suggests that, given piceatannol's various mechanisms to accomplish its pleiotropic activities, it may be able to counteract any senescent phenotypes.
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Senescencia Celular/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Senoterapéuticos/farmacología , Estilbenos/farmacología , Envejecimiento/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , HumanosRESUMEN
Senotherapeutics are new drugs that can modulate senescence phenomena within tissues and reduce the onset of age-related pathologies. Senotherapeutics are divided into senolytics and senomorphics. The senolytics selectively kill senescent cells, while the senomorphics delay or block the onset of senescence. Metformin has been used to treat diabetes for several decades. Recently, it has been proposed that metformin may have anti-aging properties as it prevents DNA damage and inflammation. We evaluated the senomorphic effect of 6 weeks of therapeutic metformin treatment on the biology of human adipose mesenchymal stromal cells (MSCs). The study was combined with a proteome analysis of changes occurring in MSCs' intracellular and secretome protein composition in order to identify molecular pathways associated with the observed biological phenomena. The metformin reduced the replicative senescence and cell death phenomena associated with prolonged in vitro cultivation. The continuous metformin supplementation delayed and/or reduced the impairment of MSC functions as evidenced by the presence of three specific pathways in metformin-treated samples: 1) the alpha-adrenergic signaling, which contributes to regulation of MSCs physiological secretory activity, 2) the signaling pathway associated with MSCs detoxification activity, and 3) the aspartate degradation pathway for optimal energy production. The senomorphic function of metformin seemed related to its reactive oxygen species (ROS) scavenging activity. In metformin-treated samples, the CEBPA, TP53 and USF1 transcription factors appeared to be involved in the regulation of several factors (SOD1, SOD2, CAT, GLRX, GSTP1) blocking ROS.
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Mesenchymal stromal cells (MSCs) are currently used for cartilage cell therapy because of their well proven capacity to differentiate in chondrocytes. The advantage of MSC-based therapy is the possibility of producing a high number of chondrocytes for implants. The transplant procedure, however, has some limitations, since MSCs may produce non-functional chondrocytes. This limit has been challenged by cultivating MSC in media with hydrogels containing hyaluronic acid (HA), extractive chondroitin sulfate (CS), or bio-fermentative unsulphated chondroitin (BC) alone or in combination. Nevertheless, a clear study of the effect of glycosaminoglycans (GAGs) on chondrocyte differentiation is still lacking, especially for the newly obtained unsulfated chondroitin of biotechnological origin. Are these GAGs playing a role in the commitment of stem cells to chondrocyte progenitors and in the differentiation of progenitors to mature chondrocytes? Alternatively, do they have a role only in one of these biological processes? We evaluated the role of HA, CS, and - above all - BC in cell commitment and chondrocyte differentiation of MSCs by supplementing these GAGs in different phases of in vitro cultivation. Our data provided evidence that a combination of HA and CS or of HA and BC supplemented during the terminal in vitro differentiation and not during cell commitment of MSCs improved chondrocytes differentiation without the presence of fibrosis (reduced expression of Type I collagen). This result suggests that a careful evaluation of extracellular cues for chondrocyte differentiation is fundamental to obtaining a proper maturation process.
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The cells present in the stromal compartment of many tissues are a heterogeneous population containing stem cells, progenitor cells, fibroblasts, and other stromal cells. A SSEA3(+) cell subpopulation isolated from human stromal compartments showed stem cell properties. These cells, known as multilineage-differentiating stress-enduring (MUSE) cells, are capable of resisting stress and possess an excellent ability to repair DNA damage. We isolated MUSE cells from different mouse stromal compartments, such as those present in bone marrow, subcutaneous white adipose tissue, and ear connective tissue. These cells showed overlapping in vitro biological properties. The mouse MUSE cells were positive for stemness markers such as SOX2, OCT3/4, and NANOG. They also expressed TERT, the catalytic telomerase subunit. The mouse MUSE cells showed spontaneous commitment to differentiation in meso/ecto/endodermal derivatives. The demonstration that multilineage stem cells can be isolated from an animal model, such as the mouse, could offer a valid alternative to the use of other stem cells for disease studies and envisage of cellular therapies.
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Tejido Adiposo/citología , Células de la Médula Ósea/citología , Compartimento Celular , Separación Celular , Células del Tejido Conectivo/citología , Oído/anatomía & histología , Células Madre/citología , Animales , Biomarcadores/metabolismo , Ciclo Celular , Diferenciación Celular , Ectodermo/citología , Endodermo/citología , Mesodermo/citología , Ratones Endogámicos C57BL , Células del Estroma/citologíaRESUMEN
During their life span, cells have two possible states: a non-cycling, quiescent state (G0) and a cycling, activated state. Cells may enter a reversible G0 state of quiescence or, alternatively, they may undergo an irreversible G0 state. The latter may be a physiological differentiation or, following a stress event, a senescent status. Discrimination among the several G0 states represents a significant investigation, since quiescence, differentiation, and senescence are progressive phenomena with intermediate transitional stages. We used the expression of Ki67, RPS6, and beta-galactosidase to identify healthy cells that progressively enter and leave quiescence through G0-entry, G0 and G0-alert states. We then evaluated how cells may enter senescence following a genotoxic stressful event. We identified an initial stress stage with the expression of beta-galactosidase and Ki67 proliferation marker. Cells may recover from stress events or become senescent passing through early and late senescence states. Discrimination between quiescence and senescence was based on the expression of RPS6, a marker of active protein synthesis that is present in senescent cells but absent in quiescent cells. Even taking into account that fixed G0 states do not exist, our molecular algorithm may represent a method for identifying turning points of G0 transitional states that continuously change.
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Ciclo Celular , Senescencia Celular , Antígeno Ki-67/metabolismo , Proteína S6 Ribosómica/metabolismo , Estrés Fisiológico , beta-Galactosidasa/metabolismo , Humanos , Modelos Biológicos , FenotipoRESUMEN
Muse cells are adult stem cells that are present in the stroma of several organs and possess an enduring capacity to cope with endogenous and exogenous genotoxic stress. In cell therapy, the peculiar biological properties of Muse cells render them a possible natural alternative to mesenchymal stromal cells (MSCs) or to in vitro-generated pluripotent stem cells (iPSCs). Indeed, some studies have proved that Muse cells can survive in adverse microenvironments, such as those present in damaged/injured tissues. We performed an evaluation of Muse cells' proteome under basic conditions and followed oxidative stress treatment in order to identify ontologies, pathways, and networks that can be related to their enduring stress capacity. We executed the same analysis on iPSCs and MSCs, as a comparison. The Muse cells are enriched in several ontologies and pathways, such as endosomal vacuolar trafficking related to stress response, ubiquitin and proteasome degradation, and reactive oxygen scavenging. In Muse cells, the protein-protein interacting network has two key nodes with a high connectivity degree and betweenness: NFKB and CRKL. The protein NFKB is an almost-ubiquitous transcription factor related to many biological processes and can also have a role in protecting cells from apoptosis during exposure to a variety of stressors. CRKL is an adaptor protein and constitutes an integral part of the stress-activated protein kinase (SAPK) pathway. The identified pathways and networks are all involved in the quality control of cell components and may explain the stress resistance of Muse cells.
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Células Madre Adultas/citología , Células Madre Adultas/metabolismo , Proteoma/metabolismo , Proteómica , Estrés Fisiológico , Línea Celular , Daño del ADN , Ontología de Genes , Humanos , Células Madre Pluripotentes Inducidas/citología , Mapas de Interacción de Proteínas , Transducción de SeñalRESUMEN
Brown-like adipocytes can be induced in white fat depots by a different environmental or drug stimuli, known as "browning" or "beiging". These brite adipocytes express thermogenin UCP1 protein and show different metabolic advantages, such as the ability to acquire a thermogenic phenotype corresponding to standard brown adipocytes that counteracts obesity. In this research, we evaluated the effects of several browning agents during white adipocyte differentiation of bone marrow-derived mesenchymal stromal cells (MSCs). Our in vitro findings identified two compounds that may warrant further in vivo investigation as possible anti-obesity drugs. We found that rosiglitazone and sildenafil are the most promising drug candidates for a browning treatment of obesity. These drugs are already available on the market for treating diabetes and erectile dysfunction, respectively. Thus, their off-label use may be contemplated, but it must be emphasized that some severe side effects are associated with use of these drugs.
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Adipogénesis , Tejido Adiposo Blanco/patología , Reacción de Maillard , Células Madre Mesenquimatosas/citología , Obesidad/patología , Adipogénesis/genética , Apoptosis , Biomarcadores/metabolismo , Proliferación Celular , Senescencia Celular , Regulación de la Expresión Génica , Humanos , Gotas Lipídicas/metabolismo , Mitocondrias/metabolismo , Consumo de Oxígeno , Proteína Desacopladora 1/metabolismoRESUMEN
The mesenchymal stromal cells (MSCs) residing within the stromal component of visceral adipose tissue appear to be greatly affected by obesity, with impairment of their functions and presence of senescence. To gain further insight into these phenomena, we analyzed the changes in total proteome content and secretome of mouse MSCs after a high-fat diet (HFD) treatment compared to a normal diet (ND). In healthy conditions, MSCs are endowed with functions mainly devoted to vesicle trafficking. These cells have an immunoregulatory role, affecting leukocyte activation and migration, acute inflammation phase response, chemokine signaling, and platelet activities. They also present a robust response to stress. We identified four signaling pathways (TGF-ß, VEGFR2, HMGB1, and Leptin) that appear to govern the cells' functions. In the obese mice, MSCs showed a change in their functions. The immunoregulation shifted toward pro-inflammatory tasks with the activation of interleukin-1 pathway and of Granzyme A signaling. Moreover, the methionine degradation pathway and the processing of capped intronless pre-mRNAs may be related to the inflammation process. The signaling pathways we identified in ND MSCs were replaced by MET, WNT, and FGFR2 signal transduction, which may play a role in promoting inflammation, cancer, and aging.