Cell therapy for bone fracture repair: A comparative preclinical review of mesenchymal stromal cells from bone marrow and from adipose tissue

Over the last decade, there has been an increasing interest among researchers for human mesenchymal stromal cells (MSC). Their regenerative properties, multilineage differentiation capacity and immunomodulatory properties make them promising candidates for treatment in various conditions. Emerging biotechnology companies specialized in cellular and regenerative therapies have been focusing their interest on MSC-based therapies, and their use in clinical trials has steadily increased. Notably, MSC are currently tested in clinical trials addressing unmet medical needs in the field of bone fracture repair and more specifically in non-union and delayed union fractures where the bone repair process is impaired. Although MSC can be isolated from various tissues, the most commonly studied sources are bone marrow (BM) and adipose tissue (Ad). In this article, we reviewed the literature directly comparing BM- and Ad-MSC for their in vitro characteristics and in vivo osteogenic potential to determine which source of MSC would be more appropriate for bone fracture repair. As considerable variations in experimental settings between studies were found, our review was based on studies meeting specific sets of criteria, notably regarding donors’ age and gender. This review of side-by-side comparisons suggests that while BM-and Ad-MSC share common general characteristics, BM-MSC have a higher intrinsic osteogenic capacity in vitro and bone repair potential in vivo

Morphological assessment of non-human primate models of osteoarthritis: Comparisons of HR-MRI with CT arthrography (CTA)

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Functional Dicer Is Necessary for Appropriate Specification of Radial Glia during Early Development of Mouse Telencephalon

Early telencephalic development involves transformation of neuroepithelial stem cells into radial glia, which are themselves neuronal progenitors, around the time when the tissue begins to generate postmitotic neurons. To achieve this transformation, radial precursors express a specific combination of proteins. We investigate the hypothesis that micro RNAs regulate the ability of the early telencephalic progenitors to establish radial glia. We ablate functional Dicer, which is required for the generation of mature micro RNAs, by conditionally mutating the Dicer1 gene in the early embryonic telencephalon and analyse the molecular specification of radial glia as well as their progeny, namely postmitotic neurons and basal progenitors. Conditional mutation of Dicer1 from the telencephalon at around embryonic day 8 does not prevent morphological development of radial glia, but their expression of Nestin, Sox9, and ErbB2 is abnormally low. The population of basal progenitors, which are generated by the radial glia, is disorganised and expanded in Dicer1-/- dorsal telencephalon. While the proportion of cells expressing markers of postmitotic neurons is unchanged, their laminar organisation in the telencephalic wall is disrupted suggesting a defect in radial glial guided migration. We found that the laminar disruption could not be accounted for by a reduction of the population of Cajal Retzius neurons. Together, our data suggest novel roles for micro RNAs during early development of progenitor cells in the embryonic telencephalon

A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD

Transcriptional regulation of EphA7 and ephrin-A5 gene in the developing forebrain

Le cortex cérébral constitue l’une des structures les plus évoluées et complexes de notre cerveau. Sa surface est divisée en de nombreuses aires fonctionnelles. La mise en place des aires corticales dépend à la fois de facteurs intrinsèques comme la sécrétion de morphogènes ou l’expression en gradient de différents facteurs de transcription, mais elle dépend aussi de facteurs extrinsèques au cortex, en particulier l'innervation par le thalamus. Les ephrines et leurs récepteurs Eph constituent une famille multigénique de facteurs de signalisation impliqués dans divers événements clé du développement cortical où ils sont exprimés selon des profils spatio-temporels complexes. Aux stades tardifs du développement, EphA7 et l’ephrine-A5 sont exprimés en gradients complémentaires au sein de chaque territoire des aires présomptives, constituant ainsi les marqueurs les plus précoces de ces aires corticales. Par la combinaison d’approches in-vitro utilisant la technique d’électroporation focale de tranches corticales embryonnaires, puis in-vivo en utilisant la technique de transgénèse d’addition, nous avons identifié une séquence régulatrice de EphA7 appelée pA7, capable de mimer l’expression endogène de EphA7 au sein du télencéphale dorsal en développement. La lignée de souris pA7-GFP ainsi générée exprime la GFP spécifiquement au sein du télencéphale dorsal durant les stades précoces. Aux stades périnataux cette expression se régionalise au sein de la plaque corticale de chacune des aires présomptives selon des gradients récapitulant ceux observés pour EphA7. Nous avons ensuite purifié des neurones exprimant différents niveaux d’EphA7 par la technique de FACS «Fluorescence-Activated Cell Sorting » et l’analyse de leur transcriptome nous a permis de trouver un grand nombre de gènes différentiellement exprimés. Tous ceux testés par la technique d’hybridation in situ sont exprimés selon un gradient latéral fort et médial faible dans le cortex pariétal, similaire à celui d’EphA7. L’examination de leur profil au sein de cortex de souris dépourvus d’afférences thalamiques, nous a permis de conclure que l’expression de ces gènes incluant EphA7 s’établit indépendamment de celles-ci. Ainsi, notre étude a permis d'identifier un répertoire de gènes neuronaux, pouvant agir en amont ou en combinaison avec EphA7 pour contrôler les facteurs intrinsèques essentiels à l’établissement des aires corticales./The cerebral cortex is subdivided into distinct cortical areas characterized by specific patterns of gene expression and neuronal connectivity. The patterning of cortical areas is thought to be controlled by a combination of intrinsic factors that are expressed in the cortex, and external signals such as inputs from the thalamus. EphA7 is a member of the ephrin/Eph family of guidance factors that is involved in key aspects of the development of the cortex, and is expressed in several gradients within developing cortical areas. By combining in vitro transcriptional assays and mouse transgenics, we identified a regulatory element of the EphA7 promoter, named pA7, that can recapitulate salient features of the pattern of expression of EphA7 in the developing forebrain, including gradients in the cortex. Using a mouse reporter line where GFP expression recapitulates EphA7 expression, we developed a GFP-based cell sorting procedure to isolate cortical neuron populations displaying different levels of EphA7 expression. Transcriptome analysis of these populations enabled to identify a specific array of differentially expressed genes. All genes validated further in vivo were confirmed to be expressed along distinct gradients in the developing cortical plate, similarly to EphA7. The expression of these genes was unchanged in mutant mice defective for thalamocortical projections, indicating that their graded pattern is largely intrinsic to the cortex. Our study identifies a novel repertoire of cortical neuron genes that may act upstream of, or together with EphA7, to control the intrinsic patterning of cortical areas. Doctorat en Sciences biomédicales et pharmaceutiquesinfo:eu-repo/semantics/nonPublishe

Estimating Heat-Transport and Time-Delays in a Heat Exchanger

International audienceTransport and heat exchange phenomena occuring in a heat exchanger can be modeled as first-order hyperbolic partial differential equations (PDEs). Reformulating these equations as a time-delay system preserves the infinite-dimensional property of the system, yet decreases its mathematical complexity. Using a space-averaging technique and the method of characteristics, this paper proposes a time-delay system modeling of the flow temperatures of a heat exchanger. We propose to use a gradient-descent optimization method to estimate the parameters of this time-delay system, using boudary measurements of temperature in the heat exchanger. The interest of this approach is emphasized with experimental data obtained from the test-bench

Optimal Control of Mass Transport Time-Delay Model in an EGR

International audienceThis paper touches on the mass transport phenomenon in the exhaust gas recirculation (EGR) of a gasoline engine air path. It presents the control-oriented model and control design of the burned gas ratio (BGR) transport phenomenon, witnessed in the intake path of an internal combustion engine (ICE), due to the redirection of burned gases to the intake path by the low-pressure EGR (LP-EGR). Based on a nonlinear AMESim® model of the engine, the BGR in the intake manifold is modeled as a state-space (SS) output time-delay model, or alternatively as an ODE-PDE coupled system, that take into account the time delay between the moment at which the combusted gases leave the exhaust manifold and that at which they are readmitted in the intake manifold. In addition to their mass transport delay, the BGRs in the intake path are also subject to state and input inequality constraints. The objective of the control problem is to track a reference output profile of the BGR in the intake manifold, taking into account the transport delay and the state (output) and input constraints of the system. In this aim, two indirect optimal control approaches are implemented and compared, the discretize-then-optimize approach and the optimize-then-discretize approach. To account for the state inequality constraints, both methods are equipped with techniques for constrained optimization such as the augmented Lagrangian and the UZAWA methods. The necessary conditions of optimality are formulated, in each of both cases, and the resulting equations are solved numerically using the projected gradient-descent method, which ensures the non-violation of the input inequality constraints. The novelty of the work lies in considering the system's constraints and the infinite-dimensionality of the mass transport phenomenon governing it. The merits of the time-delay model and the model-based control design are illustrated on the nonlinear® AMESim model on which the mathematical model is based

NASAFYTOL® supplementation in adults hospitalized with COVID-19 infection: results from an exploratory open-label randomized controlled trial

peer reviewedObjectivesThe effect and safety of Nasafytol®, a food supplement combining curcumin, quercetin, and Vitamin D, on hospitalized COVID-19-positive patients as support to standard of care were to be assessed.MethodsThis exploratory, open-label, randomized, controlled trial was carried out among hospitalized adults with COVID-19 infection. Participants were randomly assigned to receive Nasafytol® or Fultium® control. The improvement of the clinical condition and occurrence of (serious) adverse events were evaluated. The study was registered on clincaltrials.gov with the identifier NCT04844658.ResultsTwenty-five patients received Nasafytol®, and 24 received Fultium®. Demographic characteristics were well balanced between the groups. On day 14 (or at hospital leave if < 14 days), no difference was observed between groups regarding their clinical condition, fever, or the need of oxygen therapy. At day 7, however, 19 participants had been discharged from the hospital in the Nasafytol® arm compared to 10 participants in the Fultium® arm. No participants were transferred to the ICU or died in the Nasafytol® arm, vs. 4 transfers and 1 death in the Fultium® arm. The clinical condition of participants in the Nasafytol® arm had improved, as evidenced by a decrease in the COVID-19 WHO score. Interestingly, five SAEs occurred with Fultium®, while no SAE was observed with Nasafytol®.ConclusionSupplementation with Nasafytol®, in addition to standard-of-care treatment, led to a faster discharge from the hospital, improved clinical conditions of participants, and a reduced risk of serious outcomes, including transfer to the intensive care unit or death, in patients hospitalized with COVID-19

Transcriptional mechanisms of EphA7 gene expression in the developing cerebral cortex.

The patterning of cortical areas is controlled by a combination of intrinsic factors that are expressed in the cortex and external signals such as inputs from the thalamus. EphA7 is a guidance receptor that is involved in key aspects of cortical development and is expressed in gradients within developing cortical areas. Here, we identified a regulatory element of the EphA7 promoter, named pA7, that can recapitulate salient features of the pattern of expression of EphA7, including cortical gradients. Using a pA7-Green fluorescent Protein (GFP) mouse reporter line, we isolated cortical neuron populations displaying different levels of EphA7/GFP expression. Transcriptome analysis of these populations enabled to identify many differentially expressed genes, including 26 transcription factors with putative binding sites in the pA7 element. Among these, Pbx1 was found to bind directly to the EphA7 promoter in the developing cortex. All genes validated further were confirmed to be expressed differentially in the developing cortex, similarly to EphA7. Their expression was unchanged in mutant mice defective for thalamocortical projections, indicating a transcriptional control largely intrinsic to the cortex. Our study identifies a novel repertoire of cortical neuron genes that may act upstream of, or together with EphA7, to control the patterning of cortical areas.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Comparison of HR-MRI with µCT arthrography for the morphological assessment of non-human primate models of osteoarthritis

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