Journal de la Societe de biologie最新文献

The homeostasis of continuously renewing human epidermis relies on the presence of adult stem cells, residing in the basal layer. Epidermal stem cells have been enriched and functionally characterized, but the exact location remained elusive. The human hair follicle and its pigmentation unit also cyclically regenerate from stem cells. Contrary to epidermal stem cells, human hair follicle stem cells have been localized, enriched, functionally and biochemically characterized. Their specific gene expression pattern has been established. The melanocyte stem population has also been localized and characterized. Finally, the hair follicle was found to harbor a number of other multipotent cells, which designates this unique organ as an alternative source of stem cells for tissue regeneration.

Fertilization in mammals requires an initial interaction of sperm with the oocyte envelope, the zona pellucida (ZP), before it reaches the oocyte. ZP is a highly glycosylated structure, composed of three (mouse) or four (rabbit, boar, bovine, humans...) glycoproteins. The presence of ZP around the oocyte does not allow heterospecific fertilization. This barrier is principally due to the presence of species-specific glycosylations on ZP proteins. Sperm bind ZP by means of membrane receptors which recognize carbohydrate moieties on ZP glycoproteins according to a well-precised sequential process. Upon initial attachment, spermatozoa bind ZP3/ZP4 which induces the sperm acrosome exocytosis followed by a secondary binding of acrosome reacted spermatozoa to ZP2 and by ZP penetration. The sperm receptors are adhesive proteins or integral plasma membrane proteins linked to intraspermatic signalling pathways activating the acrosome reaction. Over the last twenty years, numerous studies have been carried out to identify sperm receptors to ZP in several species, but the data in humans are still incomplete. Work initiated in our research group has identified several proteins interacting with recombinant human ZP2, ZP3 and ZP4, among which are glycolytic enzymes. These enzymes are involved in the gamete interaction by means of their affinity to sugars and not by their catalytic properties. From a clinical point of view, an observed lack or weak expression of some sperm receptors to ZP3 in cases of idiopathic infertility associated with in vitro fertilization failure suggests that knowing the molecular mechanism driving the gamete recognition can be important at the diagnostic level. Furthermore, it has been shown that proteins that mediate gamete recognition diverge rapidly, as a result of positive darwinian selection. A sexual conflict can drive co-evolution of reproductive molecules in both sexes resulting in reproductive isolation and species emergence.

Bone tissue undergoes permanent remodeling based on the coupled activity of osteoclasts resorbing old bone and osteoblasts forming a new matrix. The latter are considered as the main target of remodeling control pathways. Indeed, they have the full control of osteoclastogenesis through RANK-L / osteoprotegerin, the most critical pathway in the balance between bone formation and resorption. They also are under the effects of numerous transcription factors, especially members of the AP1 complex as well as the canonic Wnt - betacatenin pathway. Most bone tissue pathologies are mediated by alterations of these remodeling control pathways. Therefore, lots of efforts are made to modulate these factors which are very interesting potential therapeutic targets.

Embryonic stem (ES) cells are pluripotent cells able to differentiate into many cell types in vitro, thus providing a potential unlimited supply of cells for cognitive in vitro studies and cell-based therapy. We recently reported their efficient ability to recapitulate ectodermal and epidermal fates and form, in culture, a multilayered epidermis coupled with an underlying dermal compartment, similar to native skin. Thus, ES cells have the potential to recapitulate the reciprocal instructive ectodermal-mesodermal commitments, characteristic of embryonic skin formation. We clarified the function of BMP-4 in the binary neuroectodermal choice by stimulating sox-1+ neural precursors to undergo specific apoptosis while inducing epidermal differentiation. We further demonstrated that p63 stimulates ectodermal cell proliferation and is necessary for epidermal commitment. We provided further evidence that this unique cellular model provides a powerful tool to identify the molecular mechanisms controlling normal skin development and to investigate human ectodermal dysplasia congenital pathologies linked to p63 (in p63-ectodermal dysplasia human congenital pathologies). Epidermal stem cell activity has been used for years to repair skin injuries, but ex vivo keratinocyte amplification has limitations and grafted skin homeostasis is not totally satisfactory. Human ES cells raise hopes that the understanding of developmental steps leading to the generation of epidermal stem cells will once be translated into therapeutic benefit. We recently demonstrated that human embryonic stem cells can give rise to a stable somatic ectodermal cell population. Its finite population doubling, normal cell cycle kinetics and the absence of teratoma formation strongly suggest that, although derived from human embryonic stem cells, these ectodermal cells represent a clinically safe somatic cell population. They could thus be particularly useful as a source for committed, homogeneous, non-tumorigenic cell populations to be employed in clinical trials for epithelial stem cell loss.

Thyroid hormones (TH) are known to control development, body and muscle growth, as well as to determine muscle phenotype in the adult. TH affect muscle properties through nuclear receptors; they act either by a positive or a negative control on target genes that encode proteins accounting for contractile or metabolic phenotypes. Contractile activity and muscle load also affect muscle phenotype; several intracellular signaling pathways are involved in the transduction of signals related to contractile activity, including the calcineurin/NFAT pathway. Calcineurin activity is negatively controlled by MCIP-1 protein (modulatory calcineurin-interacting protein-1). We recently performed an experiment aimed at examining the specific and combined effects of the pharmacological calcineurin inhibition (using cyclosporin-A CsA administration) and thyroid hormone deficiency. The expected effects of CsA administration were only observed if TH were available, while thyroid deficiency totally blunted the muscle responses to calcineurin inhibition. In conditions of thyroid hormone deficiency, there was no response to the pharmacological inhibition of calcineurin, usually known to induce a slow-to-fast IIA transition associated with an enhancement of mitochondrial biogenesis in normothyroid rats. Moreover, thyroid deficiency markedly decreased the expression of MCIP-1 and MCIP-2 mRNA and proteins, two endogenous calcineurin inhibitors; such results clearly suggest that thyroid hormone and calcineurin pathways are interconnected.

Melanocyte stem cells have been recently localized in mice, in the outer root sheath of the lower permanent portion of the hair follicle. Specific depletion of melanocyte stem cell population is responsible for natural hair greying in aging mice and humans. Melanocyte stem cells also seem to drive the growth of malignant melanomas. A few mutations, either spontaneous or genetically engineered, accelerate the natural process of hair greying with age. These mutations allowed the identification of genes and signalling pathways controlling emergence, maintenance and/or differentiation of melanocyte stem cells. This review summarizes recent studies on the melanocyte stem cells and defines a few major unanswered questions in the field.

Articular cartilage is a connective tissue containing a single type of cells, chondrocytes, which synthesise a dense extracellular matrix, mainly composed of collagens, hyaluronic acid and proteoglycans. These macromolecules play a major role in the resistance and elastic properties of the tissue. They also favour interactions with small active substances, such as growth factors and cytokines. Chondrocytes have a low metabolic capacity in relatively hypoxic conditions and absence of vascular supply. In physiopathological conditions, such as osteoarthritis (OA), progressive and irreversible degradation of matrix components is occurring. With the aim of developing new and efficient therapies against OA, we investigated the molecular mechanisms that initiate the disease, in order to identify key-proteins. These targets should hopefully lead to the design of new drugs able to stop degradation and restore cartilage. One of the earliest molecular events in OA is the degradation of aggrecan, the most abundant proteoglycan. The glycosaminoglycan (GAG) chains, chondroitin-sulfate, attached on the core protein, are subjected to hydrolysis into smaller fragments. We were interested in the glycosyltransferases that catalyse the formation of the polysaccharidic chains, namely those involved in the common tetrasaccharidic protein linkage region, GlcAbeta1,3Galbeta1,3Galbeta 1,4Xyl-O-Serine. The galactose beta1,3-glucuronosyltransférase-I (GlcAT-I) which catalyses the final step of this primer and which is markedly repressed during OA is an attractive target in that respect. Indeed, the human recombinant enzyme was found to play a pivotal role in GAG synthesis. Moreover, overexpression of GlcAT-I in cartilage explants treated with IL1beta was able to fully counteract proteoglycan depletion induced by the cytokine. These results prompted us to investigate the structure, function and regulation of this enzyme. This study provides the basis for several therapy approaches (gene delivery, design of glycomimetics able to initiate GAG synthesis) to promote cartilage repair.