Stem cells and regenerative medicine, application in radiobiology

The objective of regenerative medicine is to replace damaged human tissues. The principle is to collect multipotent stem cells from the body, purify them, multiply them in vitro, and either inject them so that they can produce, directly in the body the tissues needed to regenerate a functional organ, or lead in vitro their differentiation to the type of the tissue to be regenerated before injecting them. It owes it development to the recent discoveries on stem cells. Perspectives include the treatment of certain cancers, diabetes, degenerative diseases, side effects of radiotherapy… Stem cells are present in all development stages, from the fertilized egg to adult cells. The source of embryonic stem cells is unlimited, and therefore they seem to be the future of regenerative medicine. However, because they come from embryos, they are also at the center of a worldwide ethical debate. Adult stem cells, however, do not raise such ethical questions, and they are already undergoing clinical studies. Although they are present in limited numbers, adult stem cells can be collected easily from three tissues : bone marrow, fat tissue and muscle. Their numbers can be increased using simple techniques. The most spectacular results are obtained with bone marrow, which has been used for over 40 years for the treatment of leukaemia. The French Institute of Radioprotection and Nuclear Safety participated in experimental studies on the clinical use of mesenchymal stem cells in the treatment of irradiated healthy tissues. Two major elements are currently revolutionizing regenerative medicine. Firstly, mesenchymal stem cells are used as therapeutic means, just like drugs, and as they elicit no rejection from the body, a single donor may be used to treat multiple recipients with a wide range of conditions. Secondly, reprogramming of differentiated adult cells produces stem cells with properties similar to those of embryonic stem cells (source of unlimited multipotent cells).La médecine régénérative a pour objectif de remplacer les tissus humains endommagés. Elle a pour principe de prélever et de purifier des cellules souches, de les multiplier in vitro, en maintenant leur multipotentialité pour les injecter ensuite dans l'organisme afin de leur faire fabriquer, directement, les tissus nécessaires à la réparation d'un organe, ou en orientant in vitro leur différenciation vers le tissu à traiter, avant de les injecter. Elle doit son essor aux récentes découvertes sur les cellules souches. Les perspectives sont le traitement de certains cancers, du diabète, des maladies dégénératives, des effets secondaires de la radiothérapie... Il existe des cellules souches à tous les stades du développement depuis l'oeuf fécondé jusqu'aux cellules souches adultes. Les cellules souches embryonnaires, parce qu'elles sont une source illimitée de cellules souches, semblent être l'avenir de la médecine régénérative. Cependant, parce qu'elles sont issues de l'embryon, elles sont au centre d'un débat éthique mondial. En revanche, les cellules souches adultes ne soulèvent pas de problèmes éthiques. Elles en sont déjà au stade de l'expérimentation clinique. Bien que présentes en nombres infimes, les cellules souches adultes sont facilement prélevées à partir de trois tissus: la moelle osseuse, le tissu adipeux et le muscle. Le nombre de leurs cellules souches peut être augmenté par des techniques simples. Le résultat le plus spectaculaire concerne la moelle osseuse, qui est utilisée depuis plus de quarante ans pour le traitement de la leucémie. L'Institut de Radioprotection et de Sûreté Nucléaire a participé à des études expérimentales contribuant à l'utilisation clinique des cellules souches mésenchymateuses dans le traitement des tissus sains irradiés. Deux éléments majeurs sont en train de révolutionner la médecine régénérative: les cellules souches mésenchymateuses sont utilisées comme moyen thérapeutique au même titre qu'un médicament et grâce à l'absence de leur rejet, un seul donneur permettrait de traiter de multiples receveurs dans de nombreuses pathologies; la reprogrammation des cellules adultes différenciées permet d'obtenir des cellules souches aux propriétés analogues à celles des cellules souches embryonnaires (sources illimitées de cellules pluripotentes)

Immuno-purification of a dimeric subcomplex of the respiratory NAHD-CoQ reductase of Rhodobacter capsulatus equivalent to the FP fraction of the mitochondrial complex I

AbstractThe Rhodobacter capsulatus genes encoding the NUOE and NUOF subunits, equivalent to the 24 kDa and 51 kDa subunits of the mammalian mitochondrial complex I, have been sequenced. According to the nucleotide sequence, the NUOE subunit is 389 amino acids long and has a molecular mass of 41.3 kDa. In comparison to the mitochondrial equivalent subunit, NUOE is extended at the C terminus by more than 150 amino acids. The NUOF subunit is 431 amino acids long and has a molecular mass of 47.1 kDa. A subcomplex containing both the NUOE and NUOF subunits was extracted by detergent treatment of R. capsulatus membranes and immuno-purified. This subcomplex is homologous to the mitochondrial FP fragment. Mass spectrometry after trypsin treatment of the NUOE subunit validates the atypical primary structure deduced from the sequence of the gene

Reconstruction du spectre directionnel de la houle

- Cette étude consiste en l'élaboration d'une procédure d'estimation du spectre directionnel de la houle, à partir des mesures de mouvement (tangage, roulis, lacet, pilonnement, embardée, cavalement) d'un navire se déplaçant en translation rectiligne uniforme. La connaissance de cet état de mer absolu doit permettre d'élaborer des lois de commande adaptatives pour la tranquillisation du navire, ainsi que d'utiliser celui-ci comme bouée de mesures océanographiques. Cependant, cette étude est menée dans le contexte de la boucle ouverte, c'est-à-dire que l'information obtenue sur l'état de la mer n'est pas utilisée en vue de la tranquillisation du navire. On propose une modélisation du système à l'aide d'une représentation dans l'espace d'état, suivie d'une procédure d'identification des paramètres de spectres directionnels paramétriques

Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells

The cytokines controlling the development of human interleukin (IL) 17–producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17–producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) β, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17–producing T cells. These data suggest that IL-12Rβ1– and STAT-3–dependent signals play a key role in the differentiation and/or expansion of human IL-17–producing T cell populations in vivo

An iconic language for the graphical representation of medical concepts

<p>Abstract</p> <p>Background</p> <p>Many medication errors are encountered in drug prescriptions, which would not occur if practitioners could remember the drug properties. They can refer to drug monographs to find these properties, however drug monographs are long and tedious to read during consultation. We propose a two-step approach for facilitating access to drug monographs. The first step, presented here, is the design of a graphical language, called VCM.</p> <p>Methods</p> <p>The VCM graphical language was designed using a small number of graphical primitives and combinatory rules. VCM was evaluated over 11 volunteer general practitioners to assess if the language is easy to learn, to understand and to use. Evaluators were asked to register their VCM training time, to indicate the meaning of VCM icons and sentences, and to answer clinical questions related to randomly generated drug monograph-like documents, supplied in text or VCM format.</p> <p>Results</p> <p>VCM can represent the various signs, diseases, physiological states, life habits, drugs and tests described in drug monographs. Grammatical rules make it possible to generate many icons by combining a small number of primitives and reusing simple icons to build more complex ones. Icons can be organized into simple sentences to express drug recommendations. Evaluation showed that VCM was learnt in 2 to 7 hours, that physicians understood 89% of the tested VCM icons, and that they answered correctly to 94% of questions using VCM (versus 88% using text, <it>p </it>= 0.003) and 1.8 times faster (<it>p </it>< 0.001).</p> <p>Conclusion</p> <p>VCM can be learnt in a few hours and appears to be easy to read. It can now be used in a second step: the design of graphical interfaces facilitating access to drug monographs. It could also be used for broader applications, including the design of interfaces for consulting other types of medical document or medical data, or, very simply, to enrich medical texts.</p

The HOXB4 Homeoprotein Promotes the Ex Vivo Enrichment of Functional Human Embryonic Stem Cell-Derived NK Cells

Human embryonic stem cells (hESCs) can be induced to differentiate into blood cells using either co-culture with stromal cells or following human embryoid bodies (hEBs) formation. It is now well established that the HOXB4 homeoprotein promotes the expansion of human adult hematopoietic stem cells (HSCs) but also myeloid and lymphoid progenitors. However, the role of HOXB4 in the development of hematopoietic cells from hESCs and particularly in the generation of hESC-derived NK-progenitor cells remains elusive. Based on the ability of HOXB4 to passively enter hematopoietic cells in a system that comprises a co-culture with the MS-5/SP-HOXB4 stromal cells, we provide evidence that HOXB4 delivery promotes the enrichment of hEB-derived precursors that could differentiate into fully mature and functional NK. These hEB-derived NK cells enriched by HOXB4 were characterized according to their CMH class I receptor expression, their cytotoxic arsenal, their expression of IFNγ and CD107a after stimulation and their lytic activity. Furthermore our study provides new insights into the gene expression profile of hEB-derived cells exposed to HOXB4 and shows the emergence of CD34+CD45RA+ precursors from hEBs indicating the lymphoid specification of hESC-derived hematopoietic precursors. Altogether, our results outline the effects of HOXB4 in combination with stromal cells in the development of NK cells from hESCs and suggest the potential use of HOXB4 protein for NK-cell enrichment from pluripotent stem cells

Mutations in STAT3 and IL12RB1 impair the development of human IL-17 producing T cells

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Biothérapie des irradiations

Biotherapies offered new hope for the treatment of radiation-induced severe tissue damage, including acute radiation syndrome (ARS) and severe, chronic radiation-induced abdomino-pelvic complications—i.e. pelvic radiation disease (PRD)—refractory to standard therapy. This work was initially applied to ARS. One approach uses ex vivo expansion to amplify non-irradiated bone marrow hematopoietic stem cells (HSCs) from patients with bone marrow aplasia. The expanded HSCs are reinjected into the patients to treat hematopoietic syndrome. Another approach taken stimulates residual hematopoiesis by targeting in vivo nonirradiated HSCs with an antibody coupled to a growth factor gene. The transfected HSCs then produce growth factors necessary for their proliferation, restoring hematopoiesis. The last approach uses growth factors to enhance proliferation of residual HSCs. In the most severe cases, none of these strategies completely reverses aplasia. The solution is to generate autologous HSCs from differentiated cells. We have produced HSCs from autologous inductive pluripotent stem cells (iPSCs) to treat bone marrow aplasia. They will be following up with an exploration of ARS-associated acute gastrointestinal subsyndrome. One avenue of cell therapy research investigates the role of mesenchymal stem cells (MSC) in the treatment of multiple organ dysfunction syndrome (MODS), also known as multiple organ failure (MOF). We have demonstrated that MSCs migrate to irradiated tissues; restore the bone marrow microenvironment, enhancing hematopoiesis; promote intestinal and hepatic regeneration; and limit muscle and skin tissue radionecrosis. We have demonstrated that MSCs migrate to damaged tissues and restore gut functions after irradiation, making them a promising tool for the medical management of radiation-induced gastrointestinal disorders. MSCs can be incorporated into the enteric mucosa and are able to repair radiation-induced intestinal damage by inhibiting ulceration. They release cytokines and growth factors such as IL-11, human hepatocyte growth factor, fibroblast growth factor 2, and insulin-like growth factors. These factors have previously been reported to facilitate intestinal mucosa repair, either through enhancement of cell proliferation or inhibition of epithelial cell apoptosis. By lowering levels of pro-inflammatory cytokines, while inducing anti-inflammatory cytokines, MSCs may also dampen systemic inflammatory response syndrome associated with radiation-induced gastrointestinal syndrome. Furthermore, MSC treatment of a target organ may affect distant tissues. MSCs regenerate the small intestine epithelium, which in turn restores the enterohepatic recirculation pathway initially damaged by irradiation. Another mechanism that should be considered is the role of cytokines and growth factors produced by MSCs homing to other organs, as in distant hepatic protection without introduction of MSCs into the liver. To consider further applications in patients, we carefully studied the side effects of MSC injection. None were observed in healthy tissue or residual tumors after radiotherapy. MSCs limited the progression of colorectal fibrosis. MSC therapy could reduce acute or chronic side effects of ionizing radiation and may be of therapeutic interest. These studies helped to provide irradiated patients with compassionate treatment for hematopoietic damage and radionecrosis of muscle and skin tissue, and also permitted treatment of four victims of accidental radiation overdose at Jean Monnet Hospital in Épinal, France. Clinical transfer of stem cell therapy for treating late side effects of pelvic radiation is currently under way. Initial participants in Phase II clinical research will be recruited in 201

Stem Cells and Irradiation

International audienceThe main difficulty of radiotherapy is to destroy cancer cells without depletion of healthy tissue [...

Rencontres de jeux régionaux : en pays niçois, en Bretagne

Projet pédagogique avec unité d'apprentissage d'une douzaine de séances sur 5 à 6 semaines et rencontres de circonscription autour de la redécouverte des jeux traditionnels, et d'un travail de recherche patrimonial régional. En pays niçois : la balle au tambourin, lo pilo; en Bretagne : bahzig kamm