Allogeneic stem cell transplantations represent perfect example of immunotherapy. Its positive aspects are due to the graft versus tumor effect. Unfortunately, this therapeutic advantage is usually associated with graft versus host effects. While the mechanism of these two graft reactions remain unclear, this is possible to modulate these immunologic effects. The type of conditioning regimen, the source of donor and the use of donor cells after the transplantation may influence the toxicity and the tumor response, leading to a better optimization of the procedure. This paper is presenting all the parameters which may contribute to improve allogeneic stem cell transplantations.

The most abundant and well-studied microbiota on the human body resides in the intestinal tract. Its impact extends the limits of the mucosal interface as it plays an essential role in systemic functions such as development of the immune system. At the level of the intestine, commensal microbes play important metabolic functions and promote the integrity of the mucosal barrier. Moreover, a large number of studies points to a role of the microbiota in intestinal regeneration both under homeostatic conditions and after epithelial damage. As intestinal regeneration is sustained by highly proliferative intestinal stem cells (ISCs), these observations raise the question of a direct impact of commensals on the activity of these cells. Key mediators of the dialog between microbes and the epithelium are the immune cells residing in the gut. Consistently, both innate lymphoid cells and macrophages activated by microbial stimuli have been shown to promote ISCs proliferation by secreting cytokines. More direct routes of communication have been described recently, either through the binding of bacterial ligands to Pattern Recognition Receptors expressed in ISCs, or through the sensing by ISCs of bacterial metabolites. In this review, we explore this stem cell-microbiota dialog and its impact on gut homeostasis.

Heart failure is a major concern for public health systems, and several approaches of cellular therapy are being investigated with the goal of improving the function of these failing hearts. Many cell types have been used (skeletal myoblasts, hematopoietic, endothelial or mesenchymal progenitors, cardiac cells…), most often in the indication of post-ischemic heart failure rather than in the indication of genetic dilated cardiomyopathy. It is easier, indeed, to target a restricted area than the whole myocardium. Several clinical trials have reported slight but encouraging functional benefits, but their interpretations were frequently limited by the small sizes of cohorts, and by the biological variabilities inherent to the patients status and to the biology of the cells. These trials also shed light on unexpected mechanisms of action of the cells, which are changing the concepts and methodologies of the studies. The functional benefits observed would be due, indeed, to the secretion of trophic factors by the cells, instead of their true structural and mechanical integration within the myocardial tissue. Accordingly, the new generations of clinical trials aim at improving the size and homogeneity of the patient cohorts to increase the statistical power. On the other hand, several studies are associating or conditionning cells with biomaterials or cocktails of cytokines to improve their survival and their biological efficacy. In parallel, bio-engineering investigates several ways to support cells in vitro and in vivo, to sustain the architectural structure of the failing myocardium, to produce ex vivo some true substitutive cardiac tissue, or to purely replace the cells by their active secreted products. Several therapeutic devices should emerge from these researches, and the choice of their respective use will be ultimately guided by the medical indication.

Within the context of the SFGM-TC's 6th workshop series on the harmonization of clinical practices, our workshop proposes a standardization of the informed consent process for hematopoietic stem cell donors and recipients leading up to an autologous or allogenic transplantation. All informed consent was for bone marrow or peripheral stem cell donors, and mononuclear/lymphocyte donors according to usual procedures. The informed consent for autologous and allogenic related or unrelated adults and pediatric transplantation patients have been included. A first step has been conducted for collecting in advance the informed consent forms used routinely in all francophone transplantation centers. In a second step, a comprehensive version has been re-written by a multidisciplinary team. For the purposes of understanding the risks and advantages, language has been carefully considered and streamlined. In the third step, texts were sent to stem cell transplantation experts, experts at the French biomedical agency (agence de la biomédecine [ABM]), law specialists, members of the ethical committee of the French society of hematology and several transplant recipients to be edited and proofread.

Haploidentical hematopoietic stem cell transplantation (HSCT) is being increasingly used due to improvement of the transplantation procedures allowing a reduction of graft-versus-host-disease (GVHD) and of transplant-related mortality (TRM). Such improvements have been particularly observed after administration of T-replete HSCT graft associated to an in vivo T cell depletion by the administration of high-doses of cyclophosphamide (HD-Cy) after transplantation. Here, we have analyzed the results of haplo-identical T replete HSC transplants, in particular, when performed with post-transplant HD-Cy in order to provide recommendations for the clinical practice. Criteria of choice for a haploidentical donor by priority order are absence of donor-specific antibodies (DSA) and to prioritize: CMV seronegative recipient/donor couples, ABO matching in case of deserythrocytation, male donor for a male recipient, the youngest donor. There is no clear argument in favor of the use of bone marrow versus peripheral blood stem cells (PBSC) after non myeloablative conditioning regimen, while after ablative conditioning PBSC seem to be associated with higher risks of GVHD without obvious impact on survival. Results of haploidentical HSCT, confirmed by several groups, are interesting in lymphomas (in particular Hodgkin disease) and for acute leukemia. Outcomes of patients rely on age, disease status at transplant and conditioning intensity. At equivalent disease risk, results of haploidentical HSCT seem comparable to those of HLA matched HSCT, raising the question of the classification of such transplants as alternatives. In all cases, we recommend to include patients in prospective clinical trials.

Alport syndrome is an inherited disorder characterized by the association of a progressive haematuric nephropathy with ultrastructural abnormalities of the glomerular basement membranes, a progressive sensorineural hearing loss and sometimes ocular involvement. Its incidence is less than 1 per 5000 individuals and the disease is the cause of about 2% of end stage renal disease in Europe and the United States. Alport syndrome is clinically and genetically heterogeneous. It is related to mutations in the genes encoding one of three chains, α3, α4 α5 of type IV collagen, the main component of basement membranes, expressed in the glomerular basement membrane. COL4A5 mutations are associated with X-linked Alport syndrome, which represents 80 to 85% of cases and is more severe in boys than in girls. Mutations in COL4A3 or COL4A4 are associated with autosomal Alport syndrome. The expression of collagen chains in skin and kidney basement membranes allows for the diagnosis and characterization of the mode of transmission in most patients. It is necessary to diagnose this syndrome because its family involvement, its severity, and the importance of genetic counseling. Angiotensin blockers are increasingly prescribed in proteinuric patients. Prospective studies are needed to assess the effectiveness of these treatments on proteinuria and progression of kidney failure, and to specify indications. Animal studies have shown the potential value of different molecules (protease inhibitors, chemokine receptor blockers, transforming growth factor-β1 inhibitors, hydroxy-methyl-coenzyme A reductase inhibitors, bone morphogenetic protein-7 inhibitors), hematopoietic stem cells, and of a anti-micro-RNA.

To date, despite an existing regulatory framework and standards, there are no true technical recommendations. A survey of 23 cell processing facilities (France, Belgium and Switzerland) has allowed to overview current practices according to cellular products specifications upon arrival at the facility, with modalities for their preparation prior to cryopreservation, storage, thawing and finally for infusion to patient. Data analysis shows great variability of collected volumes and cell concentrations in cellular products. Despite homogeneous practices for handling cells at the facility, methods vary between centers, especially for the choice of cryoprotective solutions and thawing methods. During the workshop, practices have been discussed and summarized to write of recommendations about the following topics: processing and cryopreservation, thawing, bedside precautions (for infusion). This work identifies some improvements in terms of collection, choice of wash solution of thawed cells and validation of the conditions of carriage.

Success of allogeneic hematopoietic stem cells transplantation requires both the underlying disease eradication and satisfying reconstitution of hematopoiesis from donor cells. However, reconstitution delays, secondary development or persistence of cytopenia are regularly observed and are potential causes of failure after allogeneic transplantation. These graft dysfunctions should be distinguished from non-engraftment/engraftment failure. Although these situations are relatively common, there is no consensus in the literature for their management. During the workshop of the SFGM-TC, the working group proposed recommendations from an analysis of the literature.

The concept of high-doses chemotherapy was developed in the 1980s based on in vitro scientific observations. Exposure of tumor cells to increasing concentrations of alkylating agents resulted in increased cell death in a strong dose-response manner. Moreover, the acquired resistance of tumor cells could be overcome by dose intensification. In clinic, dose intensification of alkylating agents resulted in increased therapeutic responses, however associated with significant hematological toxicity. Following the development of autologous stem cells transplantation harvesting from peripheral blood, the high-doses of chemotherapy, initially associated with marked toxic effects, could be more easily tolerated. As a result, the approach was evaluated in different types of solid tumors, including breast, ovarian and germ cell tumors, small cell lung carcinoma, soft tissue sarcomas and Ewing sarcoma. To date, high-doses chemotherapy with hematopoietic stem cells support is only used as a salvage therapy to treat poor prognosis germ cell tumors patients with chemo-sensitive disease. Regarding breast and ovarian cancer, high-doses chemotherapy should be considered only in the context of clinical trials. However, intensive therapy as an approach to overcome resistance to standard treatments is still relevant. Numerous efforts are still ongoing to identify novel therapeutic combinations and active treatments to improve patients' responses.

Limbal stem cell deficiency is predominantly caused by severe eye burns resulting in a decreased or a complete ablation of the regenerative potential of these stem cells. The inability to reconstruct the corneal epithelium further leads conjunctivalization of the gimbal-epithelial barrier. These abnormalities collectively result in the progressive opacification of the cornea responsible for blindness that is driven by chronic corneal ulceration and neovascularization. The underlying pathology of the cornea affects the homeostasis of the neighboring conjunctiva, eyelids, and tear film. Therefore, the ocular reconstruction to treat limbal stem cell deficiency is quite prolonged and involves a continued treatment plan. The management of limbal stem cell deficiency has undergone a multitude of changes over the past several decades. The understanding of limbal anatomy and physiology, as well as therapeutic advances in the stem cell field have propelled the development of new treatments offering new hope to severely disabled patients. Cultivated limbal epithelial and oral mucosal epithelial transplantations are therefore viable alternatives that could be utilized for the treatment of limbal stem cell deficiency.

Serotonin and bone-marrow-derived stem cells participate together in triggering pulmonary hypertension. Our work has shown that the absence of 5-HT2B receptors generates permanent changes in the composition of the blood and bone-marrow in the myeloid lineages, particularly in endothelial cell progenitors. The initial functions of 5-HT2B receptors in pulmonary arterial hypertension (PAH) are restricted to bone-marrow cells. They contribute to the differentiation/proliferation/mobilization of endothelial progenitor cells from the bone-marrow. Those bone-marrow-derived cells have a critical role in the development of pulmonary hypertension and pulmonary vascular remodeling. These data indicate that bone-marrow derived endothelial progenitors play a key role in the pathogenesis of PAH and suggest that interactions involving serotonin and bone morphogenic protein type 2 receptor (BMPR2) could take place at the level of the bone-marrow.

Metastatic process is described as a "dissemination of neoplastic cells in a distant secondary site, in which cells proliferate to develop a mass of cells partially differentiated". The vast majority of death in solid cancers is the consequence of metastasis development which lead to vital organ dysfunction. In the present review, either recent discoveries or controversial subjects associated with metastasis process will be discussed. Indeed epithelia-mesenchymal transition (EMT), circulating tumor cells, tumor dormancy, colonization in distant organ and cancer stem cells are tackled.

BIOLOGICAL ASPECTS OF JAK/STAT SIGNALING IN BCR-ABL-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: Myeloproliferative disorders more recently named Myeloproliferative neoplasms (MPN) display several clinical entities: chronic myeloid leukemia (CML), the classical MPN including polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and atypical and unclassifiable NMP. The term MPN is mostly used for classical BCR-ABL-negative (myeloproliferative disorder) (ET, PV, PMF). These are clonal diseases resulting from the transformation of an hematopoietic stem cell and leading to an abnormal production of myeloid cells. The genetic defects responsible for the myeloproliferative abnormalities are called « driver » mutations and all result in deregulation of the cytokine receptor / JAK2 / STAT axis. Among them, JAK2, the thrombopoietin receptor (MPL) and calreticulin (CALR) mutations are found in around 90% of the cases. These driver MPN mutations can be associated with other driver mutations also found in other hematological malignancies, especially in PMFs. These are chronic diseases with major risks being thrombosis, hemorrhage and cytopenias for PMF and the long-term progression to myelofibrosis and the transformation to leukemia. Most recent therapeutic have focused on targeting the JAK2 signaling pathway directly by inhibitors of JAK2 or indirectly. Interferon a allows in some cases hematologic and molecular remission patients.

Becoming parents is one of the greatest wishes of a lot of couples. When their dreams come true, prior to the birth of the child, parents have to face several points: the choice of the name, place of delivery, breast or bottle feeding, etc. Recently, they have to face the issues of cord blood stem cells. Researchers and cord blood banks are also interested in those cells. In many countries a lot of advertising is made around umbilical cord blood stem cells. In France as in England, the use and preservation of cord blood are regulated by the legislators without necessarily having the same approach. The objective of this paper is to present English and French law approaches' on cord blood stem cells.

Among motor neuron diseases, spinal muscular atrophy type 1 and amyotrophic lateral sclerosis are very aggressive diseases with no cure. With the breakthrough of human induced pluripotent stem cells, iPS, researchers have now at their disposal a powerful tool to generate human motor neurons in culture and study the pathological defects in patient cells. In this review, we will see which tools for the study of patients motoneurons were developed from iPS cells and the different cellular models that were generated. We will also see how these models were validated and current research to identify new therapeutic leads.

The liver is associated with many diseases including metabolic and cholestatic diseases, cirrhosis as well as chronic and acute hepatitis. However, knowledge about the mechanisms involved in the pathophysiology of these diseases remains limited due to the restricted access to liver biopsies and the lack of cellular models derived from patients. The liver is the main organ responsible for the elimination of xenobiotics and thus hepatocytes have a key role in toxicology and pharmacokinetics. The induced pluripotent stem cells generated from patients with monogenic metabolic disorders, for which the corresponding gene is identified, are relevant in vitro models for the study of the mechanisms involved in generation of pathologies and also for drug screening. Towards this aim, robust protocols for generating liver cells, such as hepatocytes and cholangiocytes, are essential. Our study focused on familial hypercholesterolemia disease modeling, as well as on establishing a protocol for generation of functional cholangiocytes from pluripotent stem cells.