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Dive into the research topics where Brigitte Wdziekonski is active.

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Featured researches published by Brigitte Wdziekonski.


Genome Biology | 2011

Small RNA sequencing reveals miR-642a-3p as a novel adipocyte-specific microRNA and miR-30 as a key regulator of human adipogenesis

Laure-Emmanuelle Zaragosi; Brigitte Wdziekonski; Kevin Le Brigand; Phi Villageois; Bernard Mari; Rainer Waldmann; Christian Dani; Pascal Barbry

BackgroundIn severe obesity, as well as in normal development, the growth of adipose tissue is the result of an increase in adipocyte size and numbers, which is underlain by the stimulation of adipogenic differentiation of precursor cells. A better knowledge of the pathways that regulate adipogenesis is therefore essential for an improved understanding of adipose tissue expansion. As microRNAs (miRNAs) have a critical role in many differentiation processes, our study aimed to identify the role of miRNA-mediated gene silencing in the regulation of adipogenic differentiation.ResultsWe used deep sequencing to identify small RNAs that are differentially expressed during adipogenesis of adipose tissue-derived stem cells. This approach revealed the un-annotated miR-642a-3p as a highly adipocyte-specific miRNA. We then focused our study on the miR-30 family, which was also up-regulated during adipogenic differentiation and for which the role in adipogenesis had not yet been elucidated. Inhibition of the miR-30 family blocked adipogenesis, whilst over-expression of miR-30a and miR-30d stimulated this process. We additionally showed that both miR-30a and miR-30d target the transcription factor RUNX2, and stimulate adipogenesis via the modulation of this major regulator of osteogenesis.ConclusionsOverall, our data suggest that the miR-30 family plays a central role in adipocyte development. Moreover, as adipose tissue-derived stem cells can differentiate into either adipocytes or osteoblasts, the down-regulation of the osteogenesis regulator RUNX2 represents a plausible mechanism by which miR-30 miRNAs may contribute to adipogenic differentiation of adipose tissue-derived stem cells.


Molecular Therapy | 2009

Enhancement of myogenic and muscle repair capacities of human adipose-derived stem cells with forced expression of MyoD.

Sébastien Goudenege; Didier F. Pisani; Brigitte Wdziekonski; James P. Di Santo; Claude Bagnis; Christian Dani; Claude A. Dechesne

Muscle disorders such as Duchenne muscular dystrophy (DMD) still need effective treatments, and mesenchymal stem cells (MSCs) may constitute an attractive cell therapy alternative because they are multipotent and accessible in adult tissues. We have previously shown that human multipotent adipose-derived stem (hMADS) cells were able to restore dystrophin expression in the mdx mouse. The goal of this work was to improve the myogenic potential of hMADS cells and assess the impact on muscle repair. Forced expression of MyoD in vitro strongly induced myogenic differentiation while the adipogenic differentiation was inhibited. Moreover, MyoD-expressing hMADS cells had the capacity to fuse with DMD myoblasts and to restore dystrophin expression. Importantly, transplantation of these modified hMADS cells into injured muscles of immunodepressed Rag2(-/-)gammaC(-/-) mice resulted in a substantial increase in the number of hMADS cell-derived fibers. Our approach combined the easy access of MSCs from adipose tissue, the highly efficient lentiviral transduction of these cells, and the specific improvement of myogenic differentiation through the forced expression of MyoD. Altogether our results highlight the capacity of modified hMADS cells to contribute to muscle repair and their potential to deliver a repairing gene to dystrophic muscles.


Diabetes | 2014

Browning of White Adipose Cells by Intermediate Metabolites: An Adaptive Mechanism to Alleviate Redox Pressure

Audrey Carrière; Yannick Jeanson; Sandra Berger-Müller; Mireille André; Vanessa Chenouard; Emmanuelle Arnaud; Corinne Barreau; Romy Walther; Anne Galinier; Brigitte Wdziekonski; Phi Villageois; Katie Louche; Philippe Collas; Cedric Moro; Christian Dani; Francesc Villarroya; Louis Casteilla

The presence of brown adipose tissue (BAT) in human adults opens attractive perspectives to treat metabolic disorders. Indeed, BAT dissipates energy as heat via uncoupling protein (UCP)1. Brown adipocytes are located in specific deposits or can emerge among white fat through the so-called browning process. Although numerous inducers have been shown to drive this process, no study has investigated whether it could be controlled by specific metabolites. Here, we show that lactate, an important metabolic intermediate, induces browning of murine white adipose cells with expression of functional UCP1. Lactate-induced browning also occurs in human cells and in vivo. Lactate controls Ucp1 expression independently of hypoxia-inducible factor-1α and PPARα pathways but requires active PPARγ signaling. We demonstrate that the lactate effect on Ucp1 is mediated by intracellular redox modifications as a result of lactate transport through monocarboxylate transporters. Further, the ketone body β-hydroxybutyrate, another metabolite that impacts redox state, is also a strong browning inducer. Because this redox-dependent increase in Ucp1 expression promotes an oxidative phenotype with mitochondria, browning appears as an adaptive mechanism to alleviate redox pressure. Our findings open new perspectives for the control of adipose tissue browning and its physiological relevance.


Diabetes | 2010

Activin A Plays a Critical Role in Proliferation and Differentiation of Human Adipose Progenitors.

Laure Emmanuelle Zaragosi; Brigitte Wdziekonski; Phi Villageois; Mayoura Keophiphath; Marie Maumus; Tamara Tchkonia; Virginie Bourlier; Tala Mohsen-Kanson; Annie Ladoux; Christian Elabd; Marcel Scheideler; Zlatko Trajanoski; Yasuhiro Takashima; Ez-Zoubir Amri; Danièle Lacasa; Coralie Sengenès; Gérard Ailhaud; Karine Clément; Anne Bouloumié; James L. Kirkland; Christian Dani

OBJECTIVE Growth of white adipose tissue takes place in normal development and in obesity. A pool of adipose progenitors is responsible for the formation of new adipocytes and for the potential of this tissue to expand in response to chronic energy overload. However, factors controlling self-renewal of human adipose progenitors are largely unknown. We investigated the expression profile and the role of activin A in this process. RESEARCH DESIGN AND METHODS Expression of INHBA/activin A was investigated in three types of human adipose progenitors. We then analyzed at the molecular level the function of activin A during human adipogenesis. We finally investigated the status of activin A in adipose tissues of lean and obese subjects and analyzed macrophage-induced regulation of its expression. RESULTS INHBA/activin A is expressed by adipose progenitors from various fat depots, and its expression dramatically decreases as progenitors differentiate into adipocytes. Activin A regulates the number of undifferentiated progenitors. Sustained activation or inhibition of the activin A pathway impairs or promotes, respectively, adipocyte differentiation via the C/EBPβ-LAP and Smad2 pathway in an autocrine/paracrine manner. Activin A is expressed at higher levels in adipose tissue of obese patients compared with the expression levels in lean subjects. Indeed, activin A levels in adipose progenitors are dramatically increased by factors secreted by macrophages derived from obese adipose tissue. CONCLUSIONS Altogether, our data show that activin A plays a significant role in human adipogenesis. We propose a model in which macrophages that are located in adipose tissue regulate adipose progenitor self-renewal through activin A.


Stem Cells | 2010

Isolation of a Highly Myogenic CD34-Negative Subset of Human Skeletal Muscle Cells Free of Adipogenic Potential†‡§

Didier F. Pisani; Claude A. Dechesne; Sabrina Sacconi; Severine Delplace; Nathalie Belmonte; Olivia Cochet; Noémie Clement; Brigitte Wdziekonski; Albert Villageois; Catherine Butori; Claude Bagnis; James P. Di Santo; Jean-Yves Kurzenne; Claude Desnuelle; Christian Dani

The differentiation of multipotent cells into undesirable lineages is a significant risk factor when performing cell therapy. In muscular diseases, myofiber loss can be associated with progressive fat accumulation that is one of the primary factors leading to decline of muscular strength. Therefore, to avoid any contribution of injected multipotent cells to fat deposition, we have searched for a highly myogenic but nonadipogenic muscle‐derived cell population. We show that the myogenic marker CD56, which is the gold standard for myoblast‐based therapy, was unable to separate muscle cells into myogenic and adipogenic fractions. Conversely, using the stem cell marker CD34, we were able to sort two distinct populations, CD34+ and CD34−, which have been thoroughly characterized in vitro and in vivo using an immunodeficient Rag2−/−γc−/− mouse model of muscle regeneration with or without adipose deposition. Our results demonstrate that both populations have equivalent capacities for in vitro amplification. The CD34+ cells and CD34− cells exhibit equivalent myogenic potential, but only the CD34− population fails to differentiate into adipocytes in vitro and in vivo after transplantation into regenerative fat muscle. These data indicate that the muscle‐derived cells constitute a heterogeneous population of cells with various differentiation potentials. The simple CD34 sorting allows isolation of myogenic cells with no adipogenic potential and therefore could be of high interest for cell therapy when fat is accumulated in diseased muscle. STEM CELLS 2010;28:753–764


BMC Cell Biology | 2008

Effects of GSK3 inhibitors on in vitro expansion and differentiation of human adipose-derived stem cells into adipocytes

Laure-Emmanuelle Zaragosi; Brigitte Wdziekonski; Coralie Fontaine; Phi Villageois; Pascal Peraldi; Christian Dani

BackgroundMultipotent stem cells exist within adipose tissue throughout life. An abnormal recruitment of these adipose precursor cells could participate to hyperplasia of adipose tissue observed in severe obesity or to hypoplasia of adipose tissue observed in lipodystrophy. Therefore, pharmacological molecules that control the pool of stem cells in adipose tissue are of great interest. Glycogen Synthase Kinase (GSK) 3 has been previously described as involved in differentiation of preadipose cells and might be a potential therapeutic target to modulate proliferation and differentiation of adipocyte precursors. However, the impact of GSK3 inhibition on human adipose-derived stem cells remained to be investigated. The aim of this study was to investigate GSK3 as a possible target for pharmacological inhibition of stem cell adipogenesis. To reach this goal, we studied the effects of pharmacological inhibitors of GSK3, i.e. lithium chloride (LiCl) and BIO on proliferation and adipocyte differentiation of multipotent stem cells derived from human adipose tissue.ResultsOur results showed that GSK3 inhibitors inhibited proliferation and clonogenicity of human stem cells, strongly suggesting that GSK3 inhibitors could be potent regulators of the pool of adipocyte precursors in adipose tissue. The impact of GSK3 inhibition on differentiation of hMADS cells was also investigated. Adipogenic and osteogenic differentiations were inhibited upon hMADS treatment with BIO. Whereas a chronic treatment was required to inhibit osteogenesis, a treatment that was strictly restricted to the early step of differentiation was sufficient to inhibit adipogenesis.ConclusionThese results demonstrated the feasibility of a pharmacological approach to regulate adipose-derived stem cell function and that GSK3 could represent a potential target for controlling adipocyte precursor pool under conditions where fat tissue formation is impaired.


Stem Cells | 2014

Differentiation of Human Induced Pluripotent Stem Cells into Brown and White Adipocytes: Role of Pax3

Tala Mohsen-Kanson; Anne-Laure Hafner; Brigitte Wdziekonski; Yasuhiro Takashima; Phi Villageois; Audrey Carrière; Maria Svensson; Claude Bagnis; Bérengère Chignon-Sicard; Per-Arne Svensson; Louis Casteilla; Austin Smith; Christian Dani

Identification of molecular mechanisms involved in generation of different types of adipocytes is progressing substantially in mice. However, much less is known regarding characterization of brown (BAP) and white adipocyte progenitors (WAPs) in humans, highlighting the need for an in vitro model of human adipocyte development. Here, we report a procedure to selectively derive BAP and WAPs from human‐induced pluripotent stem cells. Molecular characterization of APs of both phenotypes revealed that BMP4, Hox8, Hoxc9, and HoxA5 genes were specifically expressed in WAPs, whereas expression of PRDM16, Dio2, and Pax3 marked BAPs. We focused on Pax3 and we showed that expression of this transcription factor was enriched in human perirenal white adipose tissue samples expressing UCP1 and in human classical brown fat. Finally, functional experiments indicated that Pax3 was a critical player of human AP fate as its ectopic expression led to convert WAPs into brown‐like APs. Together, these data support a model in which Pax3 is a new marker of human BAPs and a molecular mediator of their fate. The findings of this study could lead to new anti‐obesity therapies based on the recruitment of APs and constitute a platform for investigating in vitro the developmental origins of human white and brown adipocytes. Stem Cells 2014;32:1459–1467


Genome Biology | 2010

Comprehensive transcriptome analysis of mouse embryonic stem cell adipogenesis unravels new processes of adipocyte development

Nathalie Billon; Jüri Reimand; Miguel C. Monteiro; Meelis Kull; Hedi Peterson; Konstantin Tretyakov; Priit Adler; Brigitte Wdziekonski; Jaak Vilo; Christian Dani

BackgroundThe current epidemic of obesity has caused a surge of interest in the study of adipose tissue formation. While major progress has been made in defining the molecular networks that control adipocyte terminal differentiation, the early steps of adipocyte development and the embryonic origin of this lineage remain largely unknown.ResultsHere we performed genome-wide analysis of gene expression during adipogenesis of mouse embryonic stem cells (ESCs). We then pursued comprehensive bioinformatic analyses, including de novo functional annotation and curation of the generated data within the context of biological pathways, to uncover novel biological functions associated with the early steps of adipocyte development. By combining in-depth gene regulation studies and in silico analysis of transcription factor binding site enrichment, we also provide insights into the transcriptional networks that might govern these early steps.ConclusionsThis study supports several biological findings: firstly, adipocyte development in mouse ESCs is coupled to blood vessel morphogenesis and neural development, just as it is during mouse development. Secondly, the early steps of adipocyte formation involve major changes in signaling and transcriptional networks. A large proportion of the transcription factors that we uncovered in mouse ESCs are also expressed in the mouse embryonic mesenchyme and in adipose tissues, demonstrating the power of our approach to probe for genes associated with early developmental processes on a genome-wide scale. Finally, we reveal a plethora of novel candidate genes for adipocyte development and present a unique resource that can be further explored in functional assays.


Current protocols in pharmacology | 2007

Differentiation of mouse embryonic stem cells and of human adult stem cells into adipocytes.

Brigitte Wdziekonski; Phi Villageois; Christian Dani

The authors describe protocols for culture conditions in which mouse ES cells can be maintained in an undifferentiated state or committed to undergo adipocyte differentiation at a high rate and in a highly reproducible fashion. There is also a protocol for maintaining and differentiating human adult stem cells, isolated form adipose tissue and from bone marrow, into adipocytes. These culture systems provide a powerful means for studying the first step of adipose cell development and a means to investigate effects of drugs on the biology of adipocytes. There are also protocols for detection of adipocytes and analysis of their gene expression.


Archive | 2013

Development of Adipose Cells

Tala Mohsen-Kanson; Brigitte Wdziekonski; Phi Villageois; Anne-Laure Hafner; Nadège Lay; Pauline Martin; Laure-Emmanuelle Zaragosi; Nathalie Billon; Magali Plaisant; Pascal Peraldi; Annie Ladoux; Christian Dani

The current epidemic of obesity and overweight has caused a surge of interest in the study of adipose tissue formation. Much progress has been made in defining the transcriptional networks controlling the terminal differentiation of preadipocytes into mature adipocytes. However, the earliest steps that direct mesenchymal stem cells located in adipose tissue (adipose-derived stem cells (ASCs)) down the adipocyte lineage remain largely unknown. In this chapter, we first focus on the identification of intrinsic and extrinsic factors regulating thebalance between human ASC proliferation and differentiation. We point out the role of factors secreted by undifferentiated ASCs, such a FGF2, activin A, Hedgehog molecules, or secreted by adipose tissue macrophages. We also outline the role of miRNAs in these processes. In a second part, the developmental origin of adipocytes during embryogenesis is discussed. We summarize the surprising findings that have recently emerged from in vivo lineage tracing studies, unravelling unsuspected developmental origins for white adipocytes. We examine the possibility that the differential developmental origin of adipocytes could also reflect functional site-specific regulations of adipose tissue. Finally, we present human-induced pluripotent stem cells as a novel model for investigating the earliest steps of human adipocyte development.

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Dive into the Brigitte Wdziekonski's collaboration.

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Phi Villageois

University of Nice Sophia Antipolis

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Laure-Emmanuelle Zaragosi

University of Nice Sophia Antipolis

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Tala Mohsen-Kanson

University of Nice Sophia Antipolis

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Claude Bagnis

Centre national de la recherche scientifique

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Claude A. Dechesne

University of Nice Sophia Antipolis

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Gérard Ailhaud

University of Nice Sophia Antipolis

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Nathalie Belmonte

University of Nice Sophia Antipolis

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Nathalie Billon

University of Nice Sophia Antipolis

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