Le tissu adipeux : un nouveau site hématopoïétique ?

L'hématopoïèse est un processus primordial qui permet de générer en continu les cellules matures du sang tout au long de la vie d'un individu. Chez l'homme adulte, comme chez les rongeurs, la moelle osseuse (MO) a jusqu'à présent été considérée comme le tissu hématopoïétique de référence. Le tissu adipeux (TA) présente de nombreuses similitudes avec la MO qui nous ont amenés à émettre l'hypothèse selon laquelle le TA pourrait être un tissu hématopoïétique. Pour étudier le potentiel hématopoïétique d'une population cellulaire, le modèle de référence in vivo est l'irradiation suivie de la greffe de cellules. Dans un premier temps, nous nous sommes assurés que dans le TA, l'irradiation provoque comme dans la MO, une altération du compartiment hématopoïétique. Dans un second temps, nous avons analysé et caractérisé le compartiment hématopoïétique immature du TA chez la souris, qui, de façon surprenante, contient une proportion importante de cellules dont le phénotype est identique à celui des cellules souches hématopoïétiques (CSH) de moelle osseuse. Les CSH-like du TA sont fonctionnelles et présentent deux particularités étonnantes: (1) les cellules matures qui en dérivent sont uniquement des mastocytes, et (2) ces CSH-like ne semblent pas avoir migré de la MO, ce qui suggère que le tissu adipeux pourrait générer lui-même ses propres cellules hématopoïétiques. Nos résultats permettent de proposer que le tissu adipeux ne soit plus uniquement un tissu de remplissage inerte, mais un tissu dynamique constituant une source de cellules hématopoïétiques immatures majeure.Hematopoiesis is a physiological process allowing the replacement of blood cells throughout life. In humans, as in rodents, bone marrow (BM) is considered as the standard hematopoietic tissue. Adipose tissue (AT) exhibits numerous similarities with BM what have led us to propose that AT could function as an hematopoietic tissue. To study the hematopoietic potential of cell population in mice, the standard model is irradiation followed by BM cell transplantation. First, we demonstrated that irradiation induces a decrease in hematopoietic population in AT as in BM. Secondly, we analyzed and characterized the immature hematopoietic compartment of mouse AT, which surprisingly contains a very important proportion of cells, with the same phenotype than BM derived HSC. These cells are functional and present 2 striking features: (1) In our conditions, they differentiate only into mast cells, (2) they do not seem to migrate from the BM, suggesting that AT may be able to generate these hematopoietic cells by itself. Our results demonstrate that AT is not only an inert tissue able to store and release energy, but a dynamic tissue that could be a major source of immature hematopoietic cells. The identification of such cells in human AT would be of interest in cell therapy

OSIrIS: a physically based simulation tool to improve training in thermal infrared remote sensing over urban areas at high spatial resolution

International audienceThis paper describes an infrared image simulator for remote sensing applications, called OSIrIS (outdoor scene and infrared image simulation). It has been developed partly for training and reproduces with great details the physical phenomena that play a major role in complex urban environment. OSIrIS performs a synthesis of scene based on a 3-D description of the landscape with a high spatial resolution (0.5 – 10 m). The physical processes are briefly described and their importance with respect to the objectives are discussed. Thermal emission depends on temperature and generally dominates the signal. Temperature is governed by heat equation and is solved by the means of boundary conditions such as in-depth temperature and flux balance at surface. Main parameters are solar and atmospheric radiations, wind, heat conduction and changes in humidity. An innovative approach was developed to take into account variations in time of the interactions between the landscape and the physical processes. OSIrIS aims at simulating situations that are encountered in reality. It enables users self-formation, helping them understanding changes in image radiance as a function of the input parameters and their own simulation requirements. Examples are given that illustrate specific aspects of infrared images

Calcium Independent Effect of Orai1 and STIM1 in Non-Hodgkin B Cell Lymphoma Dissemination

International audienceCa 2+ release-activated Ca 2+ channels, composed of Orai1 and STIM1 (stromal interaction molecule 1) proteins, are the main Ca 2+ entry mechanism in lymphocytes. Their role in cell migration and metastasis is demonstrated in solid cancers but it remains elusive in malignant hemopathies. Diffuse large B cell lymphoma (DLBCL) is characterized by the dissemination of neoplastic B cells throughout the organism which is under the control of chemokines such as Stromal Derived Factor 1 (SDF-1) and its receptor CXCR4. CXCR4 activation triggers a complex intracellular signaling including an increase in intracellular Ca 2+ concentration whose role is still unclear. Using pharmacological and genetic approaches, we revealed that STIM1 and Orai1 were responsible for Ca 2+ influx induced by SDF-1. Furthermore, we provide in vitro and in vivo evidence that they are necessary for basal or SDF-1-induced DLBCL cell migration which is independent of Ca 2+ entry. We identify that they act as effectors coupling RhoA and ROCK dependent signaling pathway to MLC2 phosphorylation and actin polymerization. Finally, we revealed an alteration of Orai1 and STIM1 expression in extra-nodal DLBCL. Thus, we discovered a novel Ca 2+-independent but Orai1 and STIM1-dependent signaling pathway involved in basal and CXCR4 dependent cell migration, which could be relevant for DLBCL physiopathology

Adult Stromal Cells Derived from Human Adipose Tissue Provoke Pancreatic Cancer Cell Death both In Vitro and In Vivo

1932-6203 (Electronic) Journal Article Research Support, Non-U.S. Gov'tBACKGROUND: Normal tissue homeostasis is maintained by dynamic interactions between epithelial cells and their microenvironment. Disrupting this homeostasis can induce aberrant cell proliferation, adhesion, function and migration that might promote malignant behavior. Indeed, aberrant stromal-epithelial interactions contribute to pancreatic ductal adenocarcinoma (PDAC) spread and metastasis, and this raises the possibility that novel stroma-targeted therapies represent additional approaches for combating this malignant disease. The aim of the present study was to determine the effect of human stromal cells derived from adipose tissue (ADSC) on pancreatic tumor cell proliferation. PRINCIPAL FINDINGS: Co-culturing pancreatic tumor cells with ADSC and ADSC-conditioned medium sampled from different donors inhibited cancer cell viability and proliferation. ADSC-mediated inhibitory effect was further extended to other epithelial cancer-derived cell lines (liver, colon, prostate). ADSC conditioned medium induced cancer cell necrosis following G1-phase arrest, without evidence of apoptosis. In vivo, a single intra-tumoral injection of ADSC in a model of pancreatic adenocarcinoma induced a strong and long-lasting inhibition of tumor growth. CONCLUSION: These data indicate that ADSC strongly inhibit PDAC proliferation, both in vitro and in vivo and induce tumor cell death by altering cell cycle progression. Therefore, ADSC may constitute a potential cell-based therapeutic alternative for the treatment of PDAC for which no effective cure is available

Interleukin-18 produced by bone marrow- derived stromal cells supports T-cell acute leukaemia progression

International audienceDevelopment of novel therapies is critical for T-cell acute leukae-mia (T-ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T-ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T-ALL cell samples cultured on stromal cells independently of NOTCH activa-tion and maintained their ability to propagate in vivo. Similar results were obtained when T-ALL cells were cultured with ERK1/ 2-knockdown stromal cells or with conditioned medium from MEKi-treated stromal cells. Microarray analysis identified interleu-kin 18 (IL-18) as transcriptionally up-regulated in MEKi-treated MS5 cells. Recombinant IL-18 promoted T-ALL growth in vitro, whereas the loss of function of IL-18 receptor in T-ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL-18R was activated by IL-18 in blast cells. IL-18 circulating levels were increased in T-ALL-xeno-grafted mice and also in T-ALL patients in comparison with controls. This study uncovers a novel role of the pro-inflammatory cytokine IL-18 and outlines the microenvironment involvement in human T-ALL development

Le tissu adipeux (un nouveau site hématopoïétique ?)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Adipose tissue sensitivity to radiation exposure

1525-2191 (Electronic) Journal Article Research Support, Non-U.S. Gov'tTreatment of cancer using radiation can be significantly compromised by the development of severe acute and late damage to normal tissue. Treatments that either reduce the risk and severity of damage or that facilitate the healing of radiation injuries are being developed, including autologous adipose tissue grafts to repair tissue defects or involutional disorders that result from tumor resection. Adipose tissue is specialized in energy storage and contains different cell types, including preadipocytes, which could be used for autologous transplantation. It has long been considered a poorly proliferative connective tissue; however, the acute effects of ionizing radiation on adipose tissue have not been investigated. Therefore, the aim of this study was to characterize the alterations induced in adipose tissue by total body irradiation. A severe decrease in proliferating cells, as well as a significant increase in apoptotic cells, was observed in vivo in inguinal fat pads following irradiation. Additionally, irradiation altered the hematopoietic population. Decreases in the proliferation and differentiation capacities of non-hematopoietic progenitors were also observed following irradiation. Together, these data demonstrate that subcutaneous adipose tissue is very sensitive to irradiation, leading to a profound alteration of its developmental potential. This damage could also alter the reconstructive properties of adipose tissue and, therefore, calls into question its use in autologous fat transfer following radiotherapy

Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia

International audienceT-cell acute lymphoblastic leukemia (T-ALL) expands in various bonemarrow (BM) sites of the body. We investigated whether different BM sites could differently modulate T-ALL propagation using in vivo animal models. We observed that mouse and human T-ALL develop slowly in the BM of tail vertebrae compared with the BM from thorax vertebrae. T-ALL recovered from tail BM displays lower cell-surfacemarker expression and decreased metabolism and cell-cycle progression, demonstrating a dormancy phenotype. Functionally, tailderived T-ALL exhibit a deficient short-term ex vivo growth and a delayed in vivo propagation. These features are noncell-autonomous because T-ALL fromtail and thorax shares identical genomic abnormalities and functional disparities disappear in vivo and in prolonged in vitro assays. Importantly tail-derived T-ALL displays higher intrinsic resistance to cell-cycle-related drugs (ie, vincristine sulfate and cytarabine). Of note, T-ALL recovered from gonadal adipose tissues or from cocultures with adipocytes shares metabolic, cell-cycle, and phenotypic or chemoresistance features, with tail-derived T-ALL suggesting adipocytes may participate in the tail BM imprints on T-ALL. Altogether these results demonstrate that BM sites differentially orchestrate T-ALL propagation stamping specific features to leukemic cells such as quiescence and decreased response to cell-cycle-dependent chemotherapy

<i>TP53</i> alterations in primary and secondary Sézary syndrome: A diagnostic tool for the assessment of malignancy in patients with erythroderma

<div><p>Recent massive parallel sequencing data have evidenced the genetic diversity and complexity of Sézary syndrome mutational landscape with <i>TP53</i> alterations being the most prevalent genetic abnormality. We analyzed a cohort of 35 patients with SS and a control group of 8 patients with chronic inflammatory dermatoses. <i>TP53</i> status was analyzed at different clinical stages especially in 9 patients with a past-history of mycosis fungoides (MF), coined secondary SS. <i>TP53</i> mutations were only detected in 10 patients with either primary or secondary SS (29%) corresponding to point mutations, small insertions and deletions which were unique in each case. Interestingly, <i>TP53</i> mutations were both detected in sequential unselected blood mononuclear cells and in skin specimens. Cytogenetic analysis of blood specimens of 32 patients with SS showed a <i>TP53</i> deletion in 27 cases (84%). Altogether 29 out of 35 cases exhibited <i>TP53</i> mutation and/or deletion (83%). No difference in prognosis was observed according to <i>TP53</i> status while patients with secondary SS had a worse prognosis than patients with primary SS. Interestingly, patients with <i>TP53</i> alterations displayed a younger age and the presence of <i>TP53</i> alteration at initial diagnosis stage supports a pivotal oncogenic role for <i>TP53</i> mutation in SS as well as in erythrodermic MF making <i>TP53</i> assessment an ancillary method for the diagnosis of patients with erythroderma as patients with inflammatory dermatoses did not display <i>TP53</i> alteration.</p></div