Stem cells from different tissue origins share common characteristics, including selfrenewal capacity and tissue regeneration potential. Finding criteria to identify particular stem cell types, and understanding signaling pathways responsible for stemness, represent major research areas that will lead to a better characterization of the normal state of stem cells, thus improving our capability to use them for regenerative therapies. We will review here different approaches and experimental models liable to increase our knowledge of stem cells from human interfollicular epidermis. One of them, based on transcriptional profiling performed at the level of the global genome, consisted in searching universal molecular markers of stem cells. In other approaches, stem cells were studied at the level of specific characteristics. Understanding somatic stem cell properties such as quiescence or slow cycling state, and detoxification potential, led to the identification of phenotypes suitable for the selection of epidermal keratinocyte sub-populations with stem cell properties. The specific interests of these different research strategies will be discussed.

The use of epidermal stem cells and their progeny for tissue engineering and cell therapy represents a source of hope and major interest in view of applications such as replacing the loss of functionality in failing tissues or obtaining physiologic skin equivalents for skin grafting. The use of such cells necessitates the isolation and purification of rare populations of keratinocytes and then increasing their numbers by mass culture. This is not currently possible since part of the specific phenotype of these cells is lost once the cells are placed in culture. Furthermore, few techniques are available to unequivocally detect the presence of skin stem cells and/or their progeny in culture and thus quantify them. Two different sources of stem cells are currently being studied for skin research and clinical applications: skin progenitors either obtained from embryonic stem cells (ESC) or from selection from adult skin tissue. It has been shown that "keratinocyte-like" cells can be derived from ESC; however, the culturing processes must still be optimized to allow for the mass culture of homogeneous populations at a controlled stage of differentiation. The functional characterization of such populations must also be more thoroughly achieved. In order to use stem cells from adult tissues, improvements must be made in order to obtain a satisfactory degree of purification and characterization of this rare population. Distinguishing stem cells from progenitor cells at the molecular level also remains a challenge. Furthermore, stem cell research inevitably requires cultivating these cells outside their physiological environment or niche. It will thus be necessary to better understand the impact of this specific environmental niche on the preservation of the cellular phenotypes of interest.

Ex vivo cutaneous gene therapy is an alternative treatment for recessively inherited diseases with cutaneous traits. It relies on the transfer in cultured epidermal keratinocytes of the wild-type allele of the gene whose mutation is responsible for the disease. As for severely burnt patients, epithelial sheets developed from genetically corrected cells may then be grafted back to the patients. Long term correction and graft take depend on the genetic correction of stem cells. Success of such an approach has recently been reported in the case of one patient suffering from a severe case of junctional epidermolysis bullosae. Here we report a method for safely selecting keratinocytes populations after genetic manipulation. The method is non invasive and non immunogenic and allows high enrichment of genetically manipulated stem keratinocytes. This could perhaps contribute to ex vivo gene therapy approaches of cancer prone genodermatoses such as xeroderma pigmentosum.

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.

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.

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.

The peripheral nervous system (PNS) is formed by neural crest cells (NCC) that migrate out of the neural tube in early mid-gestation. NCC give rise to most components of the PNS, including sensory neurons, glial satellite cells and Schwann cells. Neural crest cells also give rise to another type of PNS cell population named boundary cap (BC) cells, that form clusters at the surface of the neural tube, at entry and exit points of peripheral nerve roots. Using various genetic tools we were able to trace BC cell progeny during development and to ablate them in vivo. This revealed a previously unsuspected function of BC cells: they are required to maintain the integrity of the spinal cord motor column as, in their absence, motor neurons translocate their cell bodies along their axons into the periphery. In addition, we found that trunk BC-derived cells migrated along peripheral axons and colonized spinal nerve roots and dorsal root ganglia (DRG). All Schwann cell precursors occupying the dorsal roots were derived from BC cells. In the DRG, BC-derived cells were the progenitors of both neurons (mainly nociceptive afferents) and satellite cells. These unexpected observations indicate that BC cells constitute a source of peripheral nervous system (PNS) components that, after the major neural crest ventrolateral migratory stream, feed a secondary wave of migration to the PNS.

Listeriosis commonly involves the central nervous system. Meningoencephalitis and rhomboencephalitis are the most frequent manifestations. Brain abscesses are rare.

The author examines the status of cancer research in the French speaking community in Belgium.

Mast cell disorders are defined by an abnormal accumulation of tissue mast cells in one or more organ systems. Clinical symptoms in mastocytosis result from mast cells derived mediators and, less frequently, from destructive infiltration of mast cells. Systemic mastocytosis is regressive among children, whereas the disease is persistent among adults. A clonal haematological non-mast cell lineage disease can be associated. The clinical course in these patients is variable ranging from asymptomatic for years to highly aggressive and rapidly devastating. Until recently, the only treatment of this incurable disease was symptomatic.

The generation of glutamatergic neurons by stem and progenitor cells is a complex process involving the tight coordination of multiple cellular activities, including cell cycle exit, initiation of neuronal differentiation and cell migration. The mechanisms that integrate these different events into a coherent program are not well understood. Here we show that the cyclin-dependent kinase inhibitor p27Kip1 plays an important role in neurogenesis in the mouse cerebral cortex, by promoting the differentiation and radial migration of cortical projection neurons. Importantly, p27Kip1 promotes neuronal differentiation and neuronal migration via two distinct mechanisms, which are themselves independent of the cell cycle regulatory function of p27Kip1. p27Kip1 inactivation by gene targeting or RNA interference results in neuronal differentiation and radial migration defects, demonstrating that p27Kip1 regulates cell migration in vivo. The differentiation defect, but not the migration defect, is rescued by overexpression of the proneural gene Neurogenin 2. p27Kip1 acts by stabilizing Neurogenin 2 protein, an activity carried by the N-terminal half of the protein. The migration defect resulting from p27Kp1 inactivation is rescued by blocking RhoA signalling, an activity that resides in the c-terminal half of p27Kip1. Thus, p27Kip1 plays a key role in cortical development, acting as a modular protein that independently regulates and couples multiple cellular pathways contributing to neurogenesis.

The management of moderate urinary incontinence after radical prostatectomy may require the use of an artificial sphincter, which remains the reference technique although it requires implantation of material, sometimes involving redo operations. Submucosal macroplastique injections have been proposed, but the results do not appear to be maintained over time. Cell therapy, consisting of the injection of stem cells into or close to the sphincter, probably represents the approach of the future, but in 2006, studies were still only at the evaluation phase.

Since 1974, umbilical cord blood (CB) has been shown to contain haematopoietic stem cells similar to stem cells from the bone marrow. In 1988, E. Gluckman and her colleagues performed - successfully - the first familial CB transplantation and cured a 5 years old child suffering from Fanconi's anemia. Rapidly, CB banks were organised throughout in the world and thanks to this novel source of haematopoietic stem cells, we can now find a donor for 75 % of the patients requiring a "bone marrow" transplantation. The major benefit of CB as a source of hematopoietic stem cells is its easy access. CB also allows a more significant degree of HLA incompatibility and thus offers an opportunity of transplantation to ethnic minorities for whom no HLA identical donors are available. However, several studies have shown that the number of cells harvested in a CB was closely correlated with the engraftment post transplantation and today, a minimum of 3.7 x 10(7) mononucleated cells/kg is recommended. This required amount of cells is not always reached due to the small volume often harvested from a CB. Therefore, to apply CB transplantations to adults, different approaches are currently being investigated : coinfusion of haploidentical cells, mesenchymal cells, a second CB, or the addition of CB expanded ex-vivo. Among these approaches, double CB transplantation seems nowadays the most promising alternative and ongoing studies should soon inform us whether the duration of aplasia will be improved.