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  • Besides their direct effect on cartilage ASCs might act on

    2018-10-22

    Besides their direct effect on cartilage, ASCs might act on the other joint tissues as synovial membrane, ligaments, meniscus and subchondral bone that are also altered in OA. Although OA is not considered an inflammatory disease, pro-inflammatory cytokines, namely IL-1β and TNF-α, are secreted by OA chondrocytes and synoviocytes and, participate to joint tissue alterations. Results from a collaborative work report that several pro-inflammatory cytokines are significantly down-regulated in chondrocytes when cultured with ASCs suggesting that ASCs may also be protective through the down-regulation of inflammatory mediators (Manferdini et al., 2013). Moreover, using the pre-clinical murine model of collagenase-induced OA, we recently described that a single ASC injection in the knee joint of mice inhibited synovial activation and formation of chondrophyte/osteophyte in joint ligaments as well as cartilage destruction, probably by suppressing synovial macrophages (Ter Huurne et al., 2012). All these data argue in favor of a trophic action of ASCs for protecting endogenous cartilage from degradation. Here, we demonstrated a pleiotropic action of ASCs on fibrosis, hypertrophy and apoptosis and, proposed HGF as one soluble mediator that participates to this overall effect. These results are promising preclinical data which confirm the interest of using ASCs in cell-based therapies for osteo-articular diseases by mediating chondroprotection in the joints of patients. Ongoing clinical trials should help addressing the efficacy of ASCs in the treatment of OA.
    Acknowledgment Work in the laboratory Inserm U844 was supported by the Inserm Institute, the University of Montpellier I and funding buy Nutlin3a from the European Community\'s seventh framework program (FP7/2007-2013) for the collaborative project: “ADIPOA: Adipose-derived stromal buy Nutlin3a for osteoarthritis treatment” and from the Agence Nationale pour la Recherche for the support of the national infrastructure: “ECELLFRANCE: Development of a national adult mesenchymal stem cell based therapy platform”. We thank the “Réseau d’Histologie Expérimentale de Montpellier” histology facility for processing our samples.
    Introduction Maintenance of the germ cell lineage ensures the passage of genetic information through generations. The initial germ cell population, known as PGCs, arises from proximal epiblast at 6.5days postcoitum (dpc) in mice (Ginsburg et al., 1990). These cells subsequently migrate to the genital ridge, and later differentiate into oocytes or spermatozoa (Ewen and Koopman, 2010; Hayashi et al., 2007; Ohinata et al., 2009; Saga, 2008; Saitou, 2009). Although the eventual process of gamete production has been intensively studied over the last century, the regulatory networks during the early stages of germ cell development, including the emergence, fate specification, migration, and differentiation of PGCs into sex-dependent gametes, remain elusive, largely due to the technical difficulties to access early embryos and the restricted number of germ cells during embryogenesis. Although several new PGC-specific genes were recently identified by gene expression analyses (Mise et al., 2008; Wang et al., 2001; Yabuta et al., 2006), to date only a few of them have been confirmed to participate in early germ cell development by gene targeting experiments, including PR-domain containing transcriptional regulators, PRDM1/BLIMP1 and PRDM14, and the DAZ family of RNA binding proteins (Ohinata et al., 2005; Ruggiu et al., 1997; Saitou, 2009; Yamaji et al., 2008). The DAZ gene family consists of BOULE, DAZ-like (DAZL), and DAZ, according to their evolutionary hierarchy. Among them, Dazl starts to express at 11.5dpc in mice, and its deficiency results in female and male infertility (Ruggiu et al., 1997). In addition, gene targeting analysis with mice on a C57BL/6 inbred background revealed a pronounced reduction of germ cells by 14.5dpc, thus suggesting that Dazl participated in early germ cell development (Lin and Page, 2005). Gill and colleagues recently showed that DAZL was required for transition of post-migrating PGCs to “gametogenesis competent cells”, a process they called “licensing” (Gill et al., 2011). PGCs in the absence of DAZL could not develop into either male or female gametes (Gill et al., 2011).