Tissue engineering is a new domain, which allows some very unique studies of many human physiological mechanisms. This technology, based on cell capacity to reproduce a three-dimensional tissue with or without the help of biomaterials, is an interesting approach to study cells in an environment quite similar to the in vivo context. This article summarizes the LOEX's (laboratory of experimental organogenesis) scientific endeavor in tissue engineering in order to better understand some physiological or pathological mechanisms. Thus wound healing, stem cells, graft vascularization and cell interactions are domains where tissue engineering has already made a significant impact.

Since the discovery of somatic stem cells different to hematopoietic stem cells, the concept of post-natal cell therapy has evolved. Among these stem cells, the human bone marrow mesenchymal stem cells represent a particularly attractive cell population for new applications in cell therapy. The purpose of this review is to summarise acquired knowledge about the bone marrow mesenchymal subsets, to raise some questions about their characterization and their physiology, and to tackle the apparently most feasible therapeutic applications and their pre-requisites.

Prognosis of acute myeloblastic leukemias (AML) remains with relapse, at a time when progress in chemotherapy regimens have increased the rate of complete remission, and improved biological tools have helped in defining diagnostic and prognostic criteria for this heterogeneous group of diseases. Allogeneic stem cell transplantation offers an example of a situation in which various immune effectors can contribute to the eradication of residual leukemic cells. However, use of allogeneic transplantation is restricted to a minority of patients. Thus, the development of immunotherapy strategies that could be used for all patients, appears highly desirable. Progress in fundamental immunology, and a better understanding of the role of the immune system in the physiopathology of leukemias now open new avenues to design innovative therapies. We here review recently published observations in this field, and propose new vaccine programs that use autologous AML blasts differentiated into dendritic cells.

Cell vaccination therapy in melanoma has now an around 15-year experience. Initially, the treatment was based on the use of autologous or allogeneic inactivated tumor cells. Today, new means become available, such as synthetic peptide tumor antigens, preparations of dendritic cells of various sorts and transfer of genes into vaccinating cells. In the protocols that have been published and that utilize dendritic cells or macrophages, about 10% of the patients show objective tumor responses. Improving the treatments requires choices among the numerous options now proposed. Pre-clinical investigations are designed to select the cell products to be tested in phase I, then II, clinical protocols. Later on, only phase-III randomized trials will confirm or not the efficacy of this new therapeutic approach.

Cellular therapy in renal cell carcinoma has to be included in a strategy based on the known sensitivity to immunotherapy of renal cell carcinoma. Cellular therapy was previously initiated with Lymphokine Activated Killer cells (LAK) then Tumor Infiltrating Lymphocytes (TIL). Yet, major clinical evaluations are performed on dendritic cells and allogeneic blood stem cell transplantation.

Donor allorecognition of the recipient after hematopoietic transplantation can result in graft-versus-host disease, a potent graft-vs-leukemia effect as well as a graft facilitation effect. Danger signals, host Ag-presenting cells and minor histocompatibility Ag have recently emerged as major determinants of such an alloreactivity. A better understanding of the involved immune mechanisms, the development of novel immunomonitoring tools and cell engineering approaches should result in a significantly increased therapeutic index of allogeneic alloreactivity.

Malignant hemopathies, although heterogeneous in their prognosis and oncogenesis, represent an interesting model for studying cancer genesis mechanisms in man through the recurrent presence of genetic abnormalities involved in oncogenesis and the availability of tumour material. Nowadays, molecular biology techniques are very much used for the diagnosis, the treatment and the follow-up of these diseases. Firstly used for research, the new techniques have completely changed our ability to characterise malignant hemopathies and to understand the cancer-inducing processes, permitting us to perform the biological assessment of patients with malignant hemopathies, the diagnosis, and to estimate and follow the outcome of patients after treatment. At a more fundamental level, the structural and functional analysis of the deregulated genes implied in leukaemia and lymphoma has improved our knowledge and understanding of oncogenic and physiologic mechanisms significantly.

High dose therapy with autologous stem cell transplantation (ASCT) has been extensively used in the past 15 years in multiple myeloma. The IFM 90 trial has shown that autologous bone marrow transplantation (BMT) is superior to conventional chemotherapy in terms of response rate, event free survival, overall survival. Several other randomized studies confirm that ASCT yields superior complete remission and event free survival rates. However, the benefit for overall survival is not always significant because some patients may receive high dose therapy at the time of relapse. While ASCT appears to be the treatment of choice for younger patients, a number of questions have been addressed in the past few years (optimal conditioning regimen, best source of stem cells, impact of tandem autotransplants, role of maintenance therapy, results of transplantation in patients over 65 years of age or with renal failure). These issues are addressed in this review. Analysis of large cohorts of patients indicate that a low beta 2 microglobulin level and the absence of chromosome 13 abnormalities are associated with a better outcome. However in patients with a high beta 2 microglobulin level and chromosome 13 abnormalities, the prognosis is poor even after tandem transplantations. Allogeneic BMT is offered to a minority of younger patients with an HLA identical sibling. Initial series have shown a high-toxic death rate and no survival advantage compared to ASCT. Yet, allogeneic BMT is possibly the only curative therapy. Reports of CR achieved after infusion of donor lymphoid cells in patients relapsing after allogeneic BMT support the concept of a graft versus myeloma effect. Therefore, the objectives of current studies are to reduce transplant related mortality by using earlier BMT, better selection of patients, better graft-versus host prophylaxis or non myeloablative conditioning regimens.

The central nervous system of adult mammals has been classically considered as structurally rigid, tightly wired, and unable to be repaired. We have shown that there exists a rather considerable degree of intrinsic plasticity due to the neurons themselves, but merely to glial cells and to multipotent stem cells. The spinal cord constitutes a good model on which we could demonstrate, with vascular and traumatic animal paradigms, that an early pharmacologic intervention could reduce significantly the extent of lesions and the subsequent functional deficit. Moreover, we showed that regeneration of severed central axons could occur, provided that the astrocytes' component of the glial scar was modified. Finally, transplants of embryonic neurons were shown to repair the axonal circuitry below a sectioned cord, and to restore reflex functions. All these data point to unprecedented perspectives of efficient therapies in acute and chronic neurological diseases.

Stem-cells have been identified in the adult human brain in two zones which are the subventricular zone and the gyrus dentatus of the hippocampus. Improvement of techniques aimed to identify, to localize and to follow the lineage of these cells have been crucial to the understanding of the following processes: a) identification of cellular proliferation, b) specific immunostaining of differentiated glial and neuronal cells, c) transplantations to decipher between intrinsic stem-cell properties and influence of the environment on the fate of the cell. Furthermore, it seems that stem-cells from other sources than the brain can differentiate into neurons both in vitro and in vivo. The aim of this review is to sum up what is known about cerebral stem-cells and the challenging tools they mean for the future.

Allogeneic transplantation of hematopoietic stem cells has potential for cure high risk malignant hematopoietic disorders. Advances in patients' supportive care and in graft versus host disease (GVHD) prevention have improved patient outcome. Although late relapses can occur, they are rare beyond 2 years after transplantation. However a prolonged follow-up is essential because of the risk of long-term complications. Some of them are life threatening (infections, secondary malignancy, chronic GVHD), others affect patient quality of life (chronic GVHD, cataract, osteonecrosis, sterility.). Fatigue, sleep disturbances and sexual dysfunction are the most common transplant related side effects and can also significantly impair patient quality of life. Despite these complications, most patients describe their quality of life as good, and consider that the benefit of the transplantation outweight its late effects.

Embryonic stem (ES) cells are pluripotential cells derived from the pre-implantation embryo. They can proliferate indefinitely in vitro while retaining pluripotency. ES cells can also be made to differentiate into a large variety of cell types in vitro. This has paved the way to research aimed at using ES-derived cells for cell replacement therapies. Hence, mouse ES cells can efficiently differentiate into neural precursors which can further generate functional neurons, astrocytes, and oligodendrocytes. Methods have also been developed to coax mouse ES-derived neural stem cells to differentiate into either dopaminergic neurons or motoneurons. Mouse ES-derived neural stem cells, or their fully differentiated progeny, have been shown to survive, integrate, and to some extent, function following transplantation within appropriate rodent host tissue. Research on human ES cells is still in its infancy. Considerable work has to be done: (1) to master growth and genetic manipulation of human ES cells; (2) to master their differentiation into specific cell types; and (3) to demonstrate that they can provide long term therapeutical benefits upon grafting into damaged tissues in humans. From the ethical point of view, the establishment of appropriate primate model will be an obligatory prerequisite to clinical trials based on ES cells derivatives grafting.

Recent unexpected observations in adult rodents that stem/progenitor cells located in the bone marrow, but also in other tissues, could, after their transplantation to an irradiated host contribute to the regeneration of damaged organs such as brain, liver, pancreas or muscle, have raised much hope for future therapeutic applications. These data have also initially been interpreted as a proof of a possible transdifferentiation or plasticity of adult stem cells located in these tissues. Additional experiments rigorously analyzed have tempered initial enthusiasm, by showing that if marrow cells do migrate in damaged muscles and liver, their contribution to organ repair is low, and in some cases, explained by cell fusion. Nevertheless, among bone marrow cells, two categories of stem cells now emerge that have a potentially tremendous interest in cell therapy, if we succeed in understanding how to purify, amplify and differentiate these more efficiently and reproducibly.