Neurotrophic Features of Human Adipose Tissue-Derived Stromal Cells: In Vitro and In Vivo Studies

Due to its abundance, easy retrieval, and plasticity characteristics, adipose-tissue-derived stromal cells (ATSCs) present unquestionable advantages over other adult-tissue-derived stem cells. Based on the in silico analysis of our previous data reporting the ATSC-specific expression profiles, the present study attempted to clarify and validate at the functional level the expression of the neurospecific genes expressed by ATSC both in vitro and in vivo. This allowed evidencing that ATSCs express neuro-specific trophins, metabolic genes, and neuroprotective molecules. They were in fact able to induce neurite outgrowth in vitro, along with tissue-specific commitment along the neural lineage and the expression of the TRKA neurotrophin receptor in vivo. Our observation adds useful information to recent evidence proposing these cells as a suitable tool for cell-based applications in neuroregenerative medicine

Soluble tumor necrosis factor receptor 1 and 2 predict outcomes in advanced chronic kidney disease : a prospective cohort study

Background : Soluble tumor necrosis factor receptors 1 (sTNFR1) and 2 (sTNFR2) have been associated to progression of renal failure, end stage renal disease and mortality in early stages of chronic kidney disease (CKD), mostly in the context of diabetic nephropathy. The predictive value of these markers in advanced stages of CKD irrespective of the specific causes of kidney disease has not yet been defined. In this study, the relationship between sTNFR1 and sTNFR2 and the risk for adverse cardiovascular events (CVE) and all-cause mortality was investigated in a population with CKD stage 4-5, not yet on dialysis, to minimize the confounding by renal function. Patients and methods : In 131 patients, CKD stage 4-5, sTNFR1, sTNFR2 were analysed for their association to a composite endpoint of all-cause mortality or first non-fatal CVE by univariate and multivariate Cox proportional hazards models. In the multivariate models, age, gender, CRP, eGFR and significant comorbidities were included as covariates. Results : During a median follow-up of 33 months, 40 events (30.5%) occurred of which 29 deaths (22.1%) and 11 (8.4%) first non-fatal CVE. In univariate analysis, the hazard ratios (HR) of sTNFR1 and sTNFR2 for negative outcome were 1.49 (95% confidence interval (CI): 1.28-1.75) and 1.13 (95% CI: 1.06-1.20) respectively. After adjustment for clinical covariables (age, CRP, diabetes and a history of cardiovascular disease) both sTNFRs remained independently associated to outcomes (HR: sTNFR1: 1.51, 95% CI: 1.30-1.77; sTNFR2: 1.13, 95% CI: 1.06-1.20). A subanalysis of the non-diabetic patients in the study population confirmed these findings, especially for sTNFR1. Conclusion : sTNFR1 and sTNFR2 are independently associated to all-cause mortality or an increased risk for cardiovascular events in advanced CKD irrespective of the cause of kidney disease

Cancer Cell Expression of Autotaxin Controls Bone Metastasis Formation in Mouse through Lysophosphatidic Acid-Dependent Activation of Osteoclasts

Bone metastases are highly frequent complications of breast cancers. Current bone metastasis treatments using powerful anti-resorptive agents are only palliative indicating that factors independent of bone resorption control bone metastasis progression. Autotaxin (ATX/NPP2) is a secreted protein with both oncogenic and pro-metastatic properties. Through its lysosphospholipase D (lysoPLD) activity, ATX controls the level of lysophosphatidic acid (LPA) in the blood. Platelet-derived LPA promotes the progression of osteolytic bone metastases of breast cancer cells. We asked whether ATX was involved in the bone metastasis process. We characterized the role of ATX in osteolytic bone metastasis formation by using genetically modified breast cancer cells exploited on different osteolytic bone metastasis mouse models.Intravenous injection of human breast cancer MDA-B02 cells with forced expression of ATX (MDA-B02/ATX) to immunodeficiency BALB/C nude mice enhanced osteolytic bone metastasis formation, as judged by increased bone loss, tumor burden, and a higher number of active osteoclasts at the metastatic site. Mouse breast cancer 4T1 cells induced the formation of osteolytic bone metastases after intracardiac injection in immunocompetent BALB/C mice. These cells expressed active ATX and silencing ATX expression inhibited the extent of osteolytic bone lesions and decreased the number of active osteoclasts at the bone metastatic site. In vitro, osteoclast differentiation was enhanced in presence of MDA-B02/ATX cell conditioned media or recombinant autotaxin that was blocked by the autotaxin inhibitor vpc8a202. In vitro, addition of LPA to active charcoal-treated serum restored the capacity of the serum to support RANK-L/MCSF-induced osteoclastogenesis.Expression of autotaxin by cancer cells controls osteolytic bone metastasis formation. This work demonstrates a new role for LPA as a factor that stimulates directly cancer growth and metastasis, and osteoclast differentiation. Therefore, targeting the autotaxin/LPA track emerges as a potential new therapeutic approach to improve the outcome of patients with bone metastases

Long-Term Safety and Efficacy of Single or Repeated Intra-Articular Injection of Allogeneic Neonatal Mesenchymal Stromal Cells for Managing Pain and Lameness in Moderate to Severe Canine Osteoarthritis Without Anti-inflammatory Pharmacological Support: Pilot Clinical Study

Objective: To explore the long-term safety and efficacy of canine allogeneic mesenchymal stromal cells (MSC) administered intra-articularly as single or repeated injections in appendicular joints of dogs affected by moderate to severe refractory osteoarthritis.Study Design: 22 pet dogs were recruited into a non-randomized, open and monocentric study initially administering one cellular injection. A second injection was offered after 6 months to owners if the first injection did not produce expected results.Materials and Methods: Anti-inflammatory treatment (if prescribed) was discontinued at last one week before the onset of treatment. Each injection consisted of at least 10 million viable neonatal allogeneic mesenchymal stromal cells obtained from fetal adnexa. Medical data was collected from veterinary clinical evaluations of joints up to 6 months post-injection and owner's assessment of their dog's mobility and well-being followed for a further 2 years when possible.Results: Mild, immediate self-limiting inflammatory joint reactions were observed in 5/22 joints after the first injection, and in almost all dogs having a subsequent injection. No other MSC-related adverse medical events were reported, neither during the 6 months follow up visits, nor during the long-term (2-years) safety follow up. Veterinary clinical evaluation showed a significant and durable clinical improvement (up to 6 months) following MSC administration. Eight dogs (11 joints) were re-injected 6 months apart, sustaining clinical benefits up to 1 year. Owner's global satisfaction reached 75% at 2 years post-treatmentConclusion: Our data suggest that a single or repeated intra-articular administration of neonatal MSC in dogs with moderate to severe OA is a safe procedure and confer clinical benefits over a 24-month period. When humoral response against MSC is investigated by flow cytometry, a positive mild and transient signal was detected in only one dog from the studied cohort, this dog having had a positive clinical outcome

ERK1 Regulates the Hematopoietic Stem Cell Niches

The mitogen-activated protein kinases (MAPK) ERK1 and ERK2 are among the major signal transduction molecules but little is known about their specific functions in vivo. ERK activity is provided by two isoforms, ERK1 and ERK2, which are ubiquitously expressed and share activators and substrates. However, there are not in vivo studies which have reported a role for ERK1 or ERK2 in HSCs and the bone marrow microenvironment. The present study shows that the ERK1-deficient mice present a mild osteopetrosis phenotype. The lodging and the homing abilities of the ERK1−/− HSC are impaired, suggesting that the ERK1−/−-defective environment may affect the engrafment of HSCs. Serial transplantations demonstrate that ERK1 is involved in the maintenance of an appropriate medullar microenvironment, but that the intrinsic properties of HSCs are not altered by the ERK1−/− defective microenvironment. Deletion of ERK1 impaired in vitro and in vivo osteoclastogenesis while osteoblasts were unaffected. As osteoclasts derive from precursors of the monocyte/macrophage lineage, investigation of the monocytic compartment was performed. In vivo analysis of the myeloid lineage progenitors revealed that the frequency of CMPs increased by approximately 1.3-fold, while the frequency of GMPs significantly decreased by almost 2-fold, compared with the respective WT compartments. The overall mononuclear-phagocyte lineage development was compromised in these mice due to a reduced expression of the M-CSF receptor on myeloid progenitors. These results show that the cellular targets of ERK1 are M-CSFR-responsive cells, upstream to osteoclasts. While ERK1 is well known to be activated by M-CSF, the present results are the first to point out an ERK1-dependent M-CSFR regulation on hematopoietic progenitors. This study reinforces the hypothesis of an active cross-talk between HSCs, their progeny and bone cells in the maintenance of the homeostasis of these compartments

First human impacts and responses of aquatic systems: a review of palaeolimnological records from around the world

Lake sediments constitute natural archives of past environmental changes. Historically, research has focused mainly on generating regional climate records, but records of human impacts caused by land use and exploitation of freshwater resources are now attracting scientific and management interests. Long-term environmental records are useful to establish ecosystem reference conditions, enabling comparisons with current environments and potentially allowing future trajectories to be more tightly constrained. Here we review the timing and onset of human disturbance in and around inland water ecosystems as revealed through sedimentary archives from around the world. Palaeolimnology provides access to a wealth of information reflecting early human activities and their corresponding aquatic ecological shifts. First human impacts on aquatic systems and their watersheds are highly variable in time and space. Landscape disturbance often constitutes the first anthropogenic signal in palaeolimnological records. While the effects of humans at the landscape level are relatively easily demonstrated, the earliest signals of human-induced changes in the structure and functioning of aquatic ecosystems need very careful investigation using multiple proxies. Additional studies will improve our understanding of linkages between human settlements, their exploitation of land and water resources, and the downstream effects on continental water

Use of Medicinal Plants in Aquaculture

Plants have been reported to produce various effects such as antistress, growth promotion, appetite stimulation, immunostimulation, aphrodisiac and to have antipathogen properties in fish and shrimp aquaculture due to their varied active principles such as alkaloids, terpenoids, tannins, saponins and flavonoids. To date, most scientific studies on the use of medicinal plants in aquaculture have focused on identification of biological activity rather than natural product determination. The plant species that have displayed the highest potential for use in aquaculture are garlic (Allium sativum), pomegranate (Punica granatum), bermuda grass (Cynodon dactylon), Indian ginseng (Whitania somnifera) and ginger (Zingiber officinale). Algae are considered to be a rich source of original bioactive molecules which display multiple bioactivities. In aquaculture, several recent studies have showed the potential of algae for the treatment of pathogens or to improve fish fitness

Exploration des compositions isotopiques en magnésium des carbonates marins comme traceurs paléoenvironnementaux

L'utilisation des compositions isotopiques en Mg des carbonates marins peut permettre l'étude du cycle biogéochimique de cet élément. Ainsi, les carbonates sont susceptibles d'enregistrer la composition isotopique de Mg de l'océan lors de leur précipitation. Cependant, il est nécessaire de comprendre les facteurs environnementaux (e.g. température, pH, Mg/Ca de la solution) qui peuvent contrôler ces compositions. Le premier objectif de cette thèse a donc été de déterminer les paramètres pouvant impacter les compositions isotopiques de Mg des carbonates par des précipitations expérimentales en conditions contrôlées. Il a ainsi été mis en évidence, dans les gammes considérées, mais qui restent restreintes, l'absence de contrôle de la température, du pH et du Mg/Ca de la solution sur le fractionnement isotopique du Mg lors de la précipitation des carbonates. Le fractionnement isotopique du Mg entre la solution et la calcite, à l'équilibre, a été évalué à -2,13 +- 0,24 pour mille (2sigma) à partir de cette étude, combinée à des données de la littérature. Ces résultats ont ensuite été appliqués à l'étude des compositions isotopiques de Mg dans des coquilles de brachiopodes à la fois modernes et anciens. Pour cela, une quantification des effets vitaux vis-à-vis des isotopes du Mg lors de la croissance du brachiopodes a été réalisée. Ainsi, les zones en équilibre isotopique pour Mg, O et C et donc susceptibles d'être utilisables lors des reconstructions paléoenvironnementales sont situées au sein de la calcite interne sur les bords de la coquille. Les premières mesures des compositions isotopiques de Mg sur les derniers 60 Ma suggèrent des variations de la composition isotopique du Mg de l'océan qui pourraient être liées à un changement du flux de carbonate à l'océanStudying the Mg isotopic composition in marine carbonate can help to understand the biogeochemical cycle of this element. Indeed, carbonates may record seawater Mg isotopic composition during their precipitation. However, it is necessary to understand the possible control of some environmental factors (e.g. temperature, pH, Mg/Ca of the solution) on those compositions. Therefore, the first goal of this thesis was to determine parameters impacting carbonate Mg isotopic composition with experimental precipitations under controlled conditions. Thus, it has been shown, in restricted ranges, that temperature, pH and solution Mg/Ca have no influence on Mg isotopic fractionation during calcite precipitation. Equilibrium Mg isotopic fractionation between solution and calcite has been evaluated to -2.13 +- 0.24 per thousand (2sigma) from this study, combined with published data. These results were then applied to a study of Mg isotopic compositions in modern and past brachiopod shells. For this, a quantification of vital effects with respect to Mg isotopes during the brachiopod growth was realized. The zones in isotopic equilibrium for Mg, O and C, and thus susceptible to be used for paleoenvironnemental reconstruction, are in the inner calcite at the edge of the shell. The first measurements of Mg isotopic compositions for the last 60 Ma suggest variations of Mg isotopic compositions of the seawater which could be linked to changes of carbonate flux in the oceanMETZ-SCD (574632105) / SudocNANCY1-Bib. numérique (543959902) / SudocNANCY2-Bibliotheque electronique (543959901) / SudocNANCY-INPL-Bib. électronique (545479901) / SudocSudocFranceF

Mg isotope fractionation during calcite precipitation: An experimental study

International audienceExperimental precipitations of calcite and other carbonate minerals were performed under various conditions of pH, temperature and solution Mg/Ca to determine the Mg partition coefficient and Mg isotope fractionation. Fifteen experiments were performed at pH ranging from 7.41 ± 0.07 to 8.51 ± 0.39, temperature ranging from 16.2 ± 0.7 to 26.5 ± 0.3°C and Mg/Ca solution ranging from 0.11 to 0.52 mol/mol. The apparent Mg partition coefficient between calcite and solution (D Mg) spans a large range of values from 0.018 ± 0.014 to 0.15 ± 0.11 and carbonate Mg isotope fractionation (D 26 Mg) ranges from À2.53 ± 0.25& to À1.33 ± 0.14& and does not correlate with either pH or temperature. The range in D Mg and D 26 Mg suggests non-equilibrium partitioning controlled by the processes of calcite growth, i.e. mixing between calcite grown at equilibrium and fluid inclusions, and entrapment of a surface Mg-rich calcite layer in isotopic equilibrium with the solution. The equilibrium Mg isotope fractionation between inorganic calcite and solution is estimated to be À2.13 ± 0.24&. Additional Mg elemental and isotopic fractionations are observed to occur during biogenic formation of calcite due to variable removal of Mg by the organisms (high-Mg calcite corals, foraminifera) of seawater Mg from their calcification medium