The myofibroblast, multiple origins for major roles in normal and pathological tissue repair

Myofibroblasts differentiate, invade and repair injured tissues by secreting and organizing the extracellular matrix and by developing contractile forces. When tissues are damaged, tissue homeostasis must be re-established, and repair mechanisms have to rapidly provide harmonious mechanical tissue organization, a process essentially supported by (myo)fibroblasts. Under physiological conditions, the secretory and contractile activities of myofibroblasts are terminated when the repair is complete (scar formation) but the functionality of the tissue is only rarely perfectly restored. At the end of the normal repair process, myofibroblasts disappear by apoptosis but in pathological situations, myofibroblasts likely remain leading to excessive scarring. Myofibroblasts originate from different precursor cells, the major contribution being from local recruitment of connective tissue fibroblasts. However, local mesenchymal stem cells, bone marrow-derived mesenchymal stem cells and cells derived from an epithelial-mesenchymal transition process, may represent alternative sources of myofibroblasts when local fibroblasts are not able to satisfy the requirement for these cells during repair. These diverse cell types probably contribute to the appearance of myofibroblast subpopulations which show specific biological properties and which are important to understand in order to develop new therapeutic strategies for treatment of fibrotic and scarring diseases

The CXCL12γ Chemokine Displays Unprecedented Structural and Functional Properties that Make It a Paradigm of Chemoattractant Proteins

The CXCL12γ chemokine arises by alternative splicing from Cxcl12, an essential gene during development. This protein binds CXCR4 and displays an exceptional degree of conservation (99%) in mammals. CXCL12γ is formed by a protein core shared by all CXCL12 isoforms, extended by a highly cationic carboxy-terminal (C-ter) domain that encompass four overlapped BBXB heparan sulfate (HS)-binding motifs. We hypothesize that this unusual domain could critically determine the biological properties of CXCL12γ through its interaction to, and regulation by extracellular glycosaminoglycans (GAG) and HS in particular. By both RT-PCR and immunohistochemistry, we mapped the localization of CXCL12γ both in mouse and human tissues, where it showed discrete differential expression. As an unprecedented feature among chemokines, the secreted CXCL12γ strongly interacted with cell membrane GAG, thus remaining mostly adsorbed on the plasmatic membrane upon secretion. Affinity chromatography and surface plasmon resonance allowed us to determine for CXCL12γ one of the higher affinity for HS (Kd = 0.9 nM) ever reported for a protein. This property relies in the presence of four canonical HS-binding sites located at the C-ter domain but requires the collaboration of a HS-binding site located in the core of the protein. Interestingly, and despite reduced agonist potency on CXCR4, the sustained binding of CXCL12γ to HS enabled it to promote in vivo intraperitoneal leukocyte accumulation and angiogenesis in matrigel plugs with much higher efficiency than CXCL12α. In good agreement, mutant CXCL12γ chemokines selectively devoid of HS-binding capacity failed to promote in vivo significant cell recruitment. We conclude that CXCL12γ features unique structural and functional properties among chemokines which rely on the presence of a distinctive C-ter domain. The unsurpassed capacity to bind to HS on the extracellular matrix would make CXCL12γ the paradigm of haptotactic proteins, which regulate essential homeostatic functions by promoting directional migration and selective tissue homing of cells

Using a modified Delphi methodology to gain consensus on the use of dressings in chronic wounds management

Objective: Managing chronic wounds is associated with a burden to patients, caregivers, health services and society and there is a lack of clarity regarding the role of dressings in improving outcomes. This study aimed to provide understanding on a range of topics, including: the definition of chronicity in wounds, the burden of illness, clinical outcomes of reducing healing time and the impact of early interventions on clinical and economic outcomes and the role of matrix metalloproteinases (MMPs) in wound healing. Method: A systematic review of the literature was carried out on the role of dressings in diabetic foot ulcer (DFU), and venous leg ulcer (VLU) management strategies, their effectiveness, associated resource use/cost, and quality of life (QoL) impact on patients. From this evidence-base statements were written regarding chronicity in wounds, burden of illness, healing time, and the role of MMPs, early interventions and dressings. A modified Delphi methodology involving two iterations of email questionnaires followed by a face-to-face meeting was used to validate the statements, in order to arrive at a consensus for each. Clinical experts were selected, representing nurses, surgeons, podiatrists, academics, and policy experts. Results: In the first round, 38/47 statements reached or exceeded the consensus threshold of 80% and none were rejected. According to the protocol, any statement not confirmed or rejected had to be modified using the comments from participants and resubmitted. In the second round, 5/9 remaining statements were confirmed and none rejected, leaving 4 to discuss at the meeting. All final statements were confirmed with at least 80% consensus. Conclusion: This modified Delphi panel sought to gain clarity from clinical experts surrounding the use of dressings in the management of chronic wounds. A full consensus statement was developed to help clinicians and policy makers improve the management of patients with these conditions

Et les paysans alors ?

Dossier : Les vrais revenus des professions libérales, commerçants, artisans et agriculteursNational audienceAnalyse des revenus agricoles sur la base des données du RICA et d'enquêtes sur des situations types. L'accent est mis sur la très grande diversité des situations

Evaluation d un effet anti-apoptotique du fibroblaste gingival et étude des mécanismes impliqués (contribution au développement d une thérapie cellulaire de l anévrisme de l aorte abdominale)

PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Etude des mécanismes régulés par les infrarouges (IR) conduisant à la protection contre la cytotoxicité induite par les ultraviolets (UV)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Inflammation gingivale au cours de la parodontite chronique (Effet du vieillissement et apport de la thérapie photodynamique)

La première partie de ce travail est une analyse comparative des tissus gingivaux inflammatoires de personnes âgées de plus de 75 ans par rapport à ceux d'adultes d'âge moyen, tous atteints de parodontite chronique. Nous montrons chez les sujets âgés: (1) un déficit en lymphocytes T CD4+, (2) une diminution des cellules de Langerhans intra-épithéliales, (3) une augmentation des cellules dendritiques dermiques, (4) une augmentation des cellules dendritiques matures, (5) une moindre dégradation du réseau collagénique et une diminution de la sécrétion de la forme active de la MMP-9. Parallèlement, nous évaluons les effets de la thérapie photodynamique (PDT) à travers l'étude de prélèvements gingivaux obtenus dans le cadre d'un essai clinique et à l'aide de tissus reconstruits in vitro. Nos résultats ne montrent pas d'effet de la PDT sur le comportement des fibroblastes en culture mais l'étude in vivo révèle l'effet immuno-modulateur de la PDT sur les tissus gingivaux inflammatoires.The first part of this work is a comparative analysis of inflammatory gingival tissues between elderly (more than 75) and middle-aged adults, with chronic periodontitis. We demonstrate in elderly: (1) a deficit in T helper lymphocytes, (2) a decrease in intraepithelial Langerhans cells, (3) an increase in dermal dendritic cells, (4) an increase in dendritic cells with a mature phenotype, (5) a lesser degradation of the collagen network associated with a decrease in the secretion of active form of MMP-9. At the same time, we evaluate the effects of PhotoDynamic Therapy (PDT) in the treatment of periodontal disease, through the analysis of gingival samples obtained in a clinical trial and of connective tissues reconstructed in vitro. Our results do not demonstrate any effect of PDT on the behavior of fibroblasts in culture; however, the clinical trial reveals the immunomodulatory effect of PDT in inflammatory gingival tissues.MONTROUGE-BUFR Odontol.PARIS5 (920492101) / SudocSudocFranceF

Rôle du fibroblaste dermique et gingival dans la cicatrisation (Modulation de l'organisation matricielle in vitro)

MONTROUGE-BUFR Odontol.PARIS5 (920492101) / SudocSudocFranceF

Modulation of keratinocyte growth factor (KGF) mRNA expression in human dermal fibroblasts grown in monolayer or within a collagen matrix

International audienceIn this study, we analysed the modulation of keratinocyte growth factor (KGF) mRNA expression in human dermal fibroblasts cultured either in monolayer or within a collagen matrix (dermal equivalent). In monolayer cultures, KGF expression by quiescent fibroblasts was stimulated by different growth substances such as serum, epidermal growth factor and basic fibroblast growth factor. Moreover, we demonstrated that the induction of this gene was mediated by at least 2 different signalling pathways involving protein kinase C (PKC) and cAMP. In dermal equivalents, we observed that the collagen matrix negatively modulated KGF mRNA expression. Indeed, among the growth substances used, only the serum slightly stimulated KGF expression. Nevertheless, as in monolayers, this induction involved at least PKC and cAMP signalling pathways. As the collagen matrix can modulate fibroblast growth, we also studied KGF expression in growing fibroblasts from either monolayer cultures or dermal equivalents. We then showed that this collagen matrix negatively influenced KGF expression independently of the proliferative state of fibroblasts. All these results underline the fact that KGF mRNA expression by human dermal fibroblasts is induced by different substances; however this expression can be modulated by fibroblast-matrix interactions