Sphingosine 1-phosphate receptor 1 is required for MMP-2 function in bone marrow mesenchymal stromal cells: implications for cytoskeleton assembly and proliferation

Bone marrow-derived mesenchymal stromal cell- (BM-MSC-) based therapy is a promising option for regenerative medicine. An important role in the control of the processes influencing the BM-MSC therapeutic efficacy, namely, extracellular matrix remodelling and proliferation and secretion ability, is played by matrix metalloproteinase- (MMP-) 2. Therefore, the identification of paracrine/autocrine regulators of MMP-2 function may be of great relevance for improving BM-MSC therapeutic potential. We recently reported that BM-MSCs release the bioactive lipid sphingosine 1-phosphate (S1P) and, here, we demonstrated an impairment of MMP-2 expression/release when the S1P receptor subtype S1PR1 is blocked. Notably, active S1PR1/MMP-2 signalling is required for F-actin structure assembly (lamellipodia, microspikes, and stress fibers) and, in turn, cell proliferation. Moreover, in experimental conditions resembling the damaged/regenerating tissue microenvironment (hypoxia), S1P/S1PR1 system is also required for HIF-1α expression and vinculin reduction. Our findings demonstrate for the first time the trophic role of S1P/S1PR1 signalling in maintaining BM-MSCs' ability to modulate MMP-2 function, necessary for cytoskeleton reorganization and cell proliferation in both normoxia and hypoxia. Altogether, these data provide new perspectives for considering S1P/S1PR1 signalling a pharmacological target to preserve BM-MSC properties and to potentiate their beneficial potential in tissue repair

Epidemiological patterns of asbestos exposure and spatial clusters of incident cases of malignant mesothelioma from the Italian national registry.

BACKGROUND: Previous ecological spatial studies of malignant mesothelioma cases, mostly based on mortality data, lack reliable data on individual exposure to asbestos, thus failing to assess the contribution of different occupational and environmental sources in the determination of risk excess in specific areas. This study aims to identify territorial clusters of malignant mesothelioma through a Bayesian spatial analysis and to characterize them by the integrated use of asbestos exposure information retrieved from the Italian national mesothelioma registry (ReNaM). METHODS: In the period 1993 to 2008, 15,322 incident cases of all-site malignant mesothelioma were recorded and 11,852 occupational, residential and familial histories were obtained by individual interviews. Observed cases were assigned to the municipality of residence at the time of diagnosis and compared to those expected based on the age-specific rates of the respective geographical area. A spatial cluster analysis was performed for each area applying a Bayesian hierarchical model. Information about modalities and economic sectors of asbestos exposure was analyzed for each cluster. RESULTS: Thirty-two clusters of malignant mesothelioma were identified and characterized using the exposure data. Asbestos cement manufacturing industries and shipbuilding and repair facilities represented the main sources of asbestos exposure, but a major contribution to asbestos exposure was also provided by sectors with no direct use of asbestos, such as non-asbestos textile industries, metal engineering and construction. A high proportion of cases with environmental exposure was found in clusters where asbestos cement plants were located or a natural source of asbestos (or asbestos-like) fibers was identifiable. Differences in type and sources of exposure can also explain the varying percentage of cases occurring in women among clusters. CONCLUSIONS: Our study demonstrates shared exposure patterns in territorial clusters of malignant mesothelioma due to single or multiple industrial sources, with major implications for public health policies, health surveillance, compensation procedures and site remediation programs

Mesenchymal Stromal Cell Secreted Sphingosine 1-Phosphate (S1P) Exerts a Stimulatory Effect on Skeletal Myoblast Proliferation.

Bone-marrow-derived mesenchymal stromal cells (MSCs) have the potential to significantly contribute to skeletal muscle healing through the secretion of paracrine factors that support proliferation and enhance participation of the endogenous muscle stem cells in the process of repair/regeneration. However, MSC-derived trophic molecules have been poorly characterized. The aim of this study was to investigate paracrine signaling effects of MSCs on skeletal myoblasts. It was found, using a biochemical and morphological approach that sphingosine 1-phosphate (S1P), a natural bioactive lipid exerting a broad range of muscle cell responses, is secreted by MSCs and represents an important factor by which these cells exert their stimulatory effects on C2C12 myoblast and satellite cell proliferation. Indeed, exposure to conditioned medium obtained from MSCs cultured in the presence of the selective sphingosine kinase inhibitor (iSK), blocked increased cell proliferation caused by the conditioned medium from untreated MSCs, and the addition of exogenous S1P in the conditioned medium from MSCs pre-treated with iSK further increased myoblast proliferation. Finally, we also demonstrated that the myoblast response to MSC-secreted vascular endothelial growth factor (VEGF) involves the release of S1P from C2C12 cells. Our data may have important implications in the optimization of cell-based strategies to promote skeletal muscle regeneration

Italian pool of asbestos workers cohorts: mortality trends of asbestos-related neoplasms after long time since first exposure

Objective Asbestos is a known human carcinogen, with evidence for malignant mesothelioma (MM), cancers of lung, ovary, larynx and possibly other organs. MM rates are predicted to increase with a power of time since first exposure (TSFE), but the possible long-term attenuation of the trend is debated. The asbestos ban enforced in Italy in 1992 gives an opportunity to measure long-term cancer risk in formerly exposed workers. Methods Pool of 43 previously studied Italian asbestos cohorts (asbestos cement, rolling stock, shipbuilding), with mortality follow-up updated to 2010. SMRs were computed for the 1970–2010 period, for the major causes, with consideration of duration and TSFE, using reference rates by age, sex, region and calendar period. Results The study included 51 801 subjects (5741 women): 55.9% alive, 42.6% died (cause known for 95%) and 1.5% lost to follow-up. Mortality was significantly increased for all deaths (SMR: men: 1.05, 95% CI 1.03 to 1.06; women: 1.17, 95% CI to 1.12 to 1.22), all malignancies combined (SMR: men: 1.17, 95% CI to 1.14 to 1.20; women: 1.33, 95% CI 1.24 to 1.43), pleural and peritoneal malignancies (SMR: men: 13.28 and 4.77, 95% CI 12.24 to 14.37 and 4.00 to 5.64; women: 28.44 and 6.75, 95% CI 23.83 to 33.69 and 4.70 to 9.39), lung (SMR: men: 1.26, 95% CI 1.21 to 1.31; women: 1.43, 95% CI 1.13 to 1.78) and ovarian cancer (SMR=1.38, 95% CI 1.00 to 1.87) and asbestosis (SMR: men: 300.7, 95% CI 270.7 to 333.2; women: 389.6, 95% CI 290.1 to 512.3). Pleural cancer rate increased during the first 40 years of TSFE and reached a plateau after. Discussion The study confirmed the increased risk for cancer of the lung, ovary, pleura and peritoneum but not of the larynx and the digestive tract. Pleural cancer mortality reached a plateau at long TSFE, coherently with recent reports

Mesenchymal stromal cells exert a stimulatory effect on skeletal myoblast proliferation through the release of Sphingosine 1-phosphate (S1P)

Bone-marrow-derived mesenchymal stromal cells (MSCs) have the potential to significantly contribute to skeletal muscle healing through the secretion of paracrine factors that support proliferation and enhance participation of the endogenous muscle stem cells in the process of repair/regeneration [1]. However, MSC-derived trophic molecules have been poorly characterized. The aim of this study was to investigate paracrine signaling effects of MSCs on skeletal myoblasts. It was found, using a biochemical and morphological approach that sphingosine 1-phosphate (S1P), a natural bioactive lipid exerting a broad range of muscle cell responses [2], is secreted by MSCs and represents an important factor by which these cells exert their stimulatory effects on C2C12 myoblast and satellite cell proliferation. Indeed, exposure to conditioned medium obtained from MSCs cultured in the presence of the selective sphingosine kinase inhibitor (iSK), blocked increased cell proliferation caused by MSCconditioned medium, and the addition of exogenous S1P in the conditioned medium from MSCs pre-treated with iSK further increased myoblast proliferation. Finally, we also demonstrated that the myoblast response to MSC-secreted vascular endothelial growth factor (VEGF) involves the release of S1P from C2C12 cells. Our data may have important implications in the optimization of cell-based strategies to promote skeletal muscle regeneration

Dinamiche temporali della mortalit\ue0 per asbestosi in coorti di lavoratori del cemento- amianto in Italia.

Introduzione Il cemento amianto \ue8 un settore lavorativo che ha comportato un\u2019esposizione occupazionale ad elevate concentrazioni di fibre di amianto. Tra i dipendenti del cemento amianto si riporta la presenza di un certo numero di lavoratori affetti da asbestosi, una malattia polmonare occupazionale causata dall'inalazione e dalla deposizione di fibre di amianto nel tessuto polmonare, la cui progressione determina disabilit\ue0, insufficienza respiratoria e morte prematura. Nei paesi occidentali il tasso di mortalit\ue0 per asbestosi \ue8 associato al passato consumo di amianto e segue dinamiche temporali correlate alla latenza. Obiettivi L\u2019obiettivo dello studio \ue8 valutare le dinamiche temporali e i determinanti associati con la mortalit\ue0 per asbestosi tra le 21 coorti osservate, costituite da lavoratori del cemento amianto esposti ad alte concentrazioni di fibre di amianto. Metodi La mortalit\ue0 per asbestosi \ue8 stata analizzata in una coorte di 13076 addetti al cemento amianto (18.1% donne). Per ogni lavoratore \ue8 stata calcolata l\u2019esposizione cumulativa sulla base della storia personale e i valori di esposizione di ciascuna azienda per anno pesando per la diversa variet\ue0 mineralogica sulla base della frazione di amianto utilizzato (Hodgson e Darnton 2010). Sono state condotte tre diverse analisi, basate su Rapporti Standardizzati di Mortalit\ue0 (RSM), modello Et\ue0- Periodo-Coorte (EPC) attraverso un modello di Poisson e analisi composizionale della mortalit\ue0 per malattie asbesto correlate (tumore primitivo pleurico e peritoneale, tumore del polmone e asbestosi). In tutte e tre le analisi si \ue8 considerata l'esposizione cumulativa. Gli RSM sono stati calcolati utilizzando i tassi di mortalit\ue0 di riferimento per regione, sesso, calendario e limitati al calcolo delle persone-anno ad eventi dopo il 1970. Risultati Le analisi si basano su 512117 anni-persona (388914 anni-persona dal 1970). La mortalit\ue0 per asbestosi raggiunge valori elevati soprattutto tra le donne (uomini RSM: 508; donne: 1027). I valori dei RSM per asbestosi aumentano rapidamente all'aumentare dell'esposizione cumulativa e con il tempo trascorso dalla prima esposizione. L'analisi EPC riporta un chiaro contributo dell'et\ue0 sulla mortalit\ue0 con un andamento crescente a partire dai 60 anni ed con un picco di mortalit\ue0 a 75-80 anni; i rischi relativi confermano l\u2019associazione con esposizione cumulativa ed \ue8 un minore rischio tra le donne.Tra i lavoratori pi\uf9 pesantemente esposti, l'asbestosi diventa la prima causa di morte per malattie asbesto-correlate tra le persone pi\uf9 anziane. Conclusioni Si conferma che la mortalit\ue0 da asbestosi \ue8 stata determinata principalmente dall'esposizione cumulativa. La differente composizione delle malattie asbesto correlate \ue8 attribuibile all'esposizione ad amianto e alla diversa abitudine al fumo tra generi. Come conseguenza del declino delle esposizioni dopo il 1980, il numero di morti per asbestosi \ue8 destinato a diminuire drasticamente nei prossimi decenni

Dinamiche temporali della mortalità per asbestosi in coorti di lavoratori del cemento- amianto in Italia

Introduzione Il cemento amianto è un settore lavorativo che ha comportato un’esposizione occupazionale ad elevate concentrazioni di fibre di amianto. Tra i dipendenti del cemento amianto si riporta la presenza di un certo numero di lavoratori affetti da asbestosi, una malattia polmonare occupazionale causata dall'inalazione e dalla deposizione di fibre di amianto nel tessuto polmonare, la cui progressione determina disabilità, insufficienza respiratoria e morte prematura. Nei paesi occidentali il tasso di mortalità per asbestosi è associato al passato consumo di amianto e segue dinamiche temporali correlate alla latenza. Obiettivi L’obiettivo dello studio è valutare le dinamiche temporali e i determinanti associati con la mortalità per asbestosi tra le 21 coorti osservate, costituite da lavoratori del cemento amianto esposti ad alte concentrazioni di fibre di amianto. Metodi La mortalità per asbestosi è stata analizzata in una coorte di 13076 addetti al cemento amianto (18.1% donne). Per ogni lavoratore è stata calcolata l’esposizione cumulativa sulla base della storia personale e i valori di esposizione diciascuna azienda per anno pesando per la diversa varietà mineralogica sulla base della frazione di amianto utilizzato (Hodgson e Darnton 2010). Sono state condotte tre diverse analisi, basate su Rapporti Standardizzati di Mortalità (RSM), modello Età- Periodo-Coorte (EPC) attraverso un modello di Poisson e analisi composizionale della mortalità per malattie asbesto correlate (tumore primitivo pleurico e peritoneale, tumore del polmone e asbestosi). In tutte e tre le analisi si è considerata l'esposizione cumulativa. Gli RSM sono stati calcolati utilizzando i tassi di mortalità di riferimento per regione, sesso, calendario e limitati al calcolo delle persone-anno ad eventi dopo il 1970. Risultati Le analisi si basano su 512117 anni-persona (388914 anni-persona dal 1970). La mortalità per asbestosi raggiunge valori elevati soprattutto tra le donne (uomini RSM: 508; donne: 1027). I valori dei RSM per asbestosi aumentano rapidamente all'aumentare dell'esposizione cumulativa e con il tempo trascorso dalla prima esposizione. L'analisi EPC riporta un chiaro contributo dell'età sulla mortalità con un andamento crescente a partire dai 60 anni ed con un picco di mortalità a 75-80 anni; i rischi relativi confermano l’associazione con esposizione cumulativa ed è un minore rischio tra le donne.Tra i lavoratori più pesantemente esposti, l'asbestosi diventa la prima causa di morte per malattie asbesto-correlate tra le persone più anziane. Conclusioni Si conferma che la mortalità da asbestosi è stata determinata principalmente dall'esposizione cumulativa. La differente composizione delle malattie asbesto correlate è attribuibile all'esposizione ad amianto e alla diversa abitudine al fumo tra generi. Come conseguenza del declino delle esposizioni dopo il 1980, il numero di morti per asbestosi è destinato a diminuire drasticamente nei prossimi decenni

Epidemiological patterns of asbestos exposure and spatial clusters of incident cases of malignant mesothelioma from the Italian national registry

Abstract BACKGROUND: Previous ecological spatial studies of malignant mesothelioma cases, mostly based on mortality data, lack reliable data on individual exposure to asbestos, thus failing to assess the contribution of different occupational and environmental sources in the determination of risk excess in specific areas. This study aims to identify territorial clusters of malignant mesothelioma through a Bayesian spatial analysis and to characterize them by the integrated use of asbestos exposure information retrieved from the Italian national mesothelioma registry (ReNaM). METHODS: In the period 1993 to 2008, 15,322 incident cases of all-site malignant mesothelioma were recorded and 11,852 occupational, residential and familial histories were obtained by individual interviews. Observed cases were assigned to the municipality of residence at the time of diagnosis and compared to those expected based on the age-specific rates of the respective geographical area. A spatial cluster analysis was performed for each area applying a Bayesian hierarchical model. Information about modalities and economic sectors of asbestos exposure was analyzed for each cluster. RESULTS: Thirty-two clusters of malignant mesothelioma were identified and characterized using the exposure data. Asbestos cement manufacturing industries and shipbuilding and repair facilities represented the main sources of asbestos exposure, but a major contribution to asbestos exposure was also provided by sectors with no direct use of asbestos, such as non-asbestos textile industries, metal engineering and construction. A high proportion of cases with environmental exposure was found in clusters where asbestos cement plants were located or a natural source of asbestos (or asbestos-like) fibers was identifiable. Differences in type and sources of exposure can also explain the varying percentage of cases occurring in women among clusters. CONCLUSIONS: Our study demonstrates shared exposure patterns in territorial clusters of malignant mesothelioma due to single or multiple industrial sources, with major implications for public health policies, health surveillance, compensation procedures and site remediation programs