This review focuses on new aspects in growth hormone (GH) biology and pathophysiology presented at the Endocrine Society's meeting, in San Diego, in June 2010. First, we will describe recent advances in the understanding of cytokine hormone signaling via STAT5 in mammary gland development, highlighting the primary role of miR193b for differentiation of mammary stem cells into alveolar progenitor cells. We will examine the potential implication of endocrine and autocrine GH for mammary gland carcinogenesis. Three novel murine models bearing tissue-specific inactivation of GH receptor or JAK2 bring new insights into the large spectrum of GH effects on energy homeostasis. We will also report new data supporting a paracrine regulation of GH secretion in women by estrogen's action in the brain. Thereafter we will question the reasons for GH abuse for doping by assessing the hormonal impact on body composition and physical performance in recreational athletes. Finally, we will discuss the controversial issue of GH replacement in acromegalic patients presenting GH deficiency after treatment of acromegaly.

It has long been known that the hedgehog signaling pathway is crucial for embryonic development, in both Drosophila and vertebrate systems. During the past few years its implication in carcinogenesis has become clear and today it is acknowledged that this pathway plays a role in the malignant transformation of multiple cell types, either owing to the mutation of some of its components or to its erratic activation. New molecular targeted therapies that inhibit the pathway have shown their unquestionable efficiency in several tumours -among which basal cell carcinoma, medulloblastoma, or pancreatic adenocarcinoma. The assessment of these inhibitors in other types of tumours is currently underway with promising results, suggesting that the Sonic hedgehog signalling pathway may become one of the therapeutic targets of the future.

Chemokines are small secreted proteins belonging to the cytokine family which were initially discovered for their chemoattractant properties for immune cells. Recently it was shown that chemokines and their G-protein-coupled receptors can be constitutively expressed or induced in several organs and different cell types. Thus chemokines have been shown to regulate immune functions involving infection and inflammation, stem cell migration during development, to be implicated in oncogenic, neovascularization and atherosclerosis processes, to modulate neuronal excitability regulating neurotransmitter release, and to play a key role in the pathogenesis of various neurodegenerative diseases such as Parkinson's disease or age-related-macular degeneration and in pain. Some of these recent advances concerning chemokine functions will be highlighted in this broad appeal symposium which aims to introduce this emerging field. This introductory chapter will examine the basic properties of the various chemokine systems and their receptors.

Mycophenolic acid (MPA) is more and more used to prevent GVHD (Graft Versus Host Disease) during hematopoietic stem cell transplantation with reduce-intensity conditioning. If several facts argue in favor of therapeutic drug monitoring, the used pharmacokinetic parameter is to be defined. Especially, the choice between total or ultrafilterable MPA is still under debate even if therapeutic drug monitoring seems to be more practicable with total MPA. The role of other factors implied in GVHD occurrence are also to be assessed in studies which aim at assessing therapeutic drug monitoring of MPA in such situation. For theses reasons, the level evidence of MPA as GVHD prophylaxis during hematopoietic stem cell transplantation with reduce-intensity conditioning is potentially useful.

Osteonecrosis of the femoral head is a rare disease that affects young patients and is characterized by the occurrence of a necrotic lesion in the femoral head, loss of mechanical resistance of dead bone and collapse of the femoral head. Patients complain of hip pain and loss of function that could lead to total hip replacement. So far, osteonecrosis was considered as a vascular disease due to vascular section or compression leading to bone necrosis. We studied the physiopathology of the osteonecrosis considering it as a bone disease. We demonstrated as well as other teams that the number of mesenchymal stem cells, precursors of bone cells and osteoblastic cells, were reduced in patients with osteonecrosis. We initiated a controlled double blind trial to study the efficacy of stem cells implantation--obtained from concentrated bone marrow--in the osteonecrosis zone. This study showed that bone marrow implantation could delay disease progression to the fractural stage and improve hip pain and joint symptoms. We then tried to improve this treatment by developing a bone cell therapy product formed of osteoblastic cells. A novel cell therapy product formed ofosteoblastic cells, PREOB was developed. PREOB was tested in a randomized, controlled phase II trial in osteonecrosis of the femoral head and showed its superiority compared to concentrated bone marrow. Today, this cellular therapy product is developed by Bone Therapeutics, a spin-offcompany of the "Université libre de Bruxelles". Other bone diseases are characterized by reduced activities of stem cells that are unable to meet the need of bone remodelling due to a non-union fracture, for example. Clinical studies also showed that concentrated bone marrow could be implanted into the non-union. However, its efficacy was dependent on the number of implanted stem cells. The cellular therapy product is currently tested in a phase I trial with promising preliminary results. Cellular therapy for bone diseases is a novel therapeutic approach that evolves from stem cells to the use of the differentiated cells of interest.

In tumours, a significant fraction of neoplastic cells are engaged in the cell cycle (growth fraction) and are therefore targets for radiation therapy and chemotherapy. Unfortunately, in most disseminated cancers, such treatments cannot lead to complete cure. Many different mechanisms have been described to explain this resistance. The hypothesis of the existence of "cancer stem cells "has been recently proposed. Indeed, the tumour would contain a small subpopulation of cancer cells displaying the phenotypical characteristics of multipotential stem cells. Since such cells display different signalling pathways compared with more differentiated cells, this might explain at least partially the resistance to treatments. Chronic myeloid leukaemia is a good model in favour of cancer stem cells, but the presence of such cells in all types of cancers is still a matter of debate. Several questions emerge: is the multipotential stem cell, the cell of origin of cancer? What is the relevance of the cancer stem cell paradigm for understanding cancer cell biology and to envision new therapeutic, hopefully curative, therapies? The case of chronic myeloid leukaemia is used to discuss these questions.

Allogeneic haematopoietic stem cell transplantation is the best treatment option for many patients suffering from severe haematologic diseases. Allogeneic transplantation is generally preceded, by a myeloablative conditioning regimen consisting of high doses of chemo/radiotherapy. The use of those high dose conditionings is restricted to young patients (< 55 years of age) without significant comorbidities. Unfortunately, median patient age at diagnosis of most haematological malignancies ranges from 60 to 70 years. It has been accepted since the late 1970s that the occurrence of acute and/or chronic graft-versus-host disease (a life-threatening complication of allogeneic transplantation consisting of host organ destruction by donor T cells present in the graft) leads to a dramatic decreased risk of relapse thanks to the destruction of host tumour cells by donor T cells (graft-versus-tumour effects). These observations led several groups of investigators to develop non-myeloablative conditionings for allogeneic haematopoietic stem cell transplantation (also termed mini-transplant) based nearly exclusively on graft-versus-tumour effects for tumour eradication. After a brief introduction, this article reviews preliminary results of nonmyeloablative transplantation and then present some perspectives aimed at increasing the efficacy while decreasing the toxicity of this approach.

Hepatocyte transplantation is considered as an alternative to organ transplantation in particular for the treatment of liver metabolic diseases. However, due to the difficulties to obtain a large number of hepatocytes, new sources of cells are needed. These cells could be either of hepatic origin (hepatic stem cells) or extrahepatic such as mesenchymal stem cells or pluripotent stem cells (human embryonic stem cells [hESC] or iPS). We developed a new method to differentiate hESCs into fetal hepatocytes. These conditions recapitulate the main liver developmental stages, using fully defined medium devoid of animal products or unknown factors. The differentiated cells express many fetal hepatocytes markers (cytochrome P450 3A7, albumin, alpha-1-antitrypsin, etc.). The cells display specific hepatic functions (ammonia metabolism, excretion of indocyanin green) and are capable to engraft and express hepatic proteins two months after transplantation into newborn uPAxrag2gc-/- mouse liver. We have also showed that this approach is transposable to human iPS, and further studies on animal models will allow us to compare the in vivo potential of these two sources of pluripotent cells. Finally, only studies on large animals such as nonhuman primates will validate an eventual clinical application.

X-linked adrenoleukodystrophy (ALD) is a severe demyelinating disease of the brain caused by a deficiency in ALD protein, an adenosine triphosphate--binding cassette (ABC) transporter encoded by the ABCD1 gene. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We have developed a gene therapy strategy based on ABCD1 gene transfer to autologous hematopoietic stem cells (CD34+) by a lentiviral vector derived from HIV-1. We initiated a clinical trial involving three ALD patients for whom no matched donor was available. Autologous CD34+ cells were transduced ex vivo with an HIV derived vector the wild-type ABCD1 gene then re-infused after myeloablative treatment. Polyclonal reconstitution was detected up to 24 to 30 months, with between 9% and 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein, strongly suggesting that the patients' hematopoietic stem cells have been successfully transduced. Cerebral demyelination halted after 14 to 16 months in two first treated patients an outcome similar to that achieved by allogeneic HCT These results suggest that lentiviral vectors are suitable for transferring therapeutic genes to hematopoietic stem cells, and provide the first example of successful gene therapy for a severe neurodegenerative disease.

The progressive neuronal loss in Alzheimer's disease leads to neurochemical abnormalities which provide the basis for symptomatic treatments. Four cholinesterase inhibitors were released in this indication. Meta-analyses have confirmed a beneficial effect on cognitive functioning and activities of daily living. The NMDA receptor antagonist, memantine, was also approved for the treatment of moderate to severe and may be associated. Progress in the patho-physiology of the disease offers some hope of new treatments acting on the cerebral lesions. The amyloid hypothesis allowed the emergence of active or passive immunotherapies, and of secretase inhibitors or modulators. Recent studies have targeted the P tau protein. The brain plasticity and the uses of stem cells offer more distant hope.

Mainly because it is possible to live without it, the spleen has always been considered a secondary and mysterious organ. However, recent observations have revealed new unsuspected functions for this organ whose patho-physiological importance should be reconsidered. Much less known than the hypersplenism, the hyposplenism corresponds historically to the loss or the insufficiency of the two principal functions of spleen: the filtration of faded or senescent elements from the blood and the fight against infections. In this article, after a short recall of the physiological functions of spleen, three innovations relating to hyposplenism will be explored: the vascular complications, the loss of the splenic pool of regenerating monocytes and the loss of the splenic pool of pluripotent mesenchymal stem cell.

Haematopoietic stem cells transplantation, widely used these last decades, represent the ultimate treatment resource for patients with haematological malignancies. Long range success of this treatment is particularly affected by relapse of the initial disease, graft rejection or graft versus host disease. Chimerism analysis after transplantation had been used since several years to document engraftment, to determine the risk of relapse and to adapt therapy promptly when necessary. Usefulness of this analysis for the outcome of transplanted patients, as well as the impact of using high sensitive techniques coupled with specific cell populations sorted have been demonstrated by retrospective studies. Follow-up of chimerism would allow to operate efficiently before the onset of clinical signs in leukaemic patients with high risk of relapse and to control the expression of minimal residual disease when specific molecular markers could not be monitored.