La fusion des macrophages : partenaires des cellules somatiques et cancéreuses ?

La fusion est un mécanisme fondamental utilisé par les organismes multicellulaires. Elle joue un rôle essentiel au cours du développement physiologique. Ainsi, la fusion est-elle le premier événement à l’origine même de la vie lors du contact fusionnel entre spermatozoïde et ovocyte. La fusion des myoblastes en myotubes participe, par la suite, à l’organisation musculaire définitive. La fusion est également rencontrée au cours de processus pathologiques. Les virus en ont fait leur quotidien pour attaquer leurs cellules cibles. La fusion macrophagique est un événement incontournable pour l’obtention de cellules ostéoclastiques et de cellules multinucléées, partenaires essentiels dans des affections comme l’ostéoporose ou les maladies inflammatoires chroniques. Pourtant, les mécanismes moléculaires impliqués dans ces différents événements sont assez mal connus. Un regain d’intérêt est néanmoins récemment apparu lorsque des cellules dérivées de la moelle osseuse ont été retrouvées différenciées en types cellulaires variés dans des tissus lésés. En effet, la fusion entre une cellule d’origine myélomonocytaire, potentiellement macrophagique, et une cellule résidente de l’organe lésé semble être à l’origine de cette plasticité inattendue. Dans cet article, Agnès Vignery revisite la fusion macrophagique et les différentes protéines qui semblent la contrôler avant de s’interroger sur la participation et la pertinence d’un mécanisme équivalent au cours de la cancérogenèse ou de la régénération tissulaire…The fusion of cells is a fundamental biological event that plays a central role in a variety of developmental and homeostatic processes. Macrophages are present in all tissues and can initiate interaction and fusion. The putative macrophage-fusion machinery is still poorly understood, but some of its components have been identified. Macrophages recognize each other as « self » in order to fuse but some essential questions remain: do macrophages fuse with somatic cells to repair tissues and organs? Do macrophages fuse with tumor cells to trigger metastasis? Agnès Vignery discusses these novel and challenging ideas in this review

Macrophage fusion: the making of osteoclasts and giant cells

The fusion of cells is a fundamental biological event that is essential for a variety of developmental and homeostatic processes. Fusion is required for the formation of multinucleated osteoclasts and giant cells, although the mechanisms that govern these processes are poorly understood. A new study now reveals an unexpected role for the receptor, dendritic cell–specific transmembrane protein (DC-STAMP), in this process. The potential mechanism by which DC-STAMP governs fusion and the implications of this finding will be discussed

Brief for AARP as Amicus Curiae in Support of Plaintiffs-Appellees and Arguing for Affirmance

Amicus ("friend of the court") brief written by Genformatic, LLC in support of petitioners in AMP v. Myriad Genetics (Case Docket No. 2010-1406)

IL-1 receptor–associated kinase M is a central regulator of osteoclast differentiation and activation

Osteoporosis is a serious problem worldwide; it is characterized by bone fractures in response to relatively mild trauma. Osteoclasts originate from the fusion of macrophages and they play a central role in bone development and remodeling via the resorption of bone. Therefore, osteoclasts are important mediators of bone loss that leads, for example, to osteoporosis. Interleukin (IL)-1 receptor (IL-1R)–associated kinase M (IRAK-M) is only expressed in cells of the myeloid lineage and it inhibits signaling downstream of IL-1R and Toll-like receptors (TLRs). However, it lacks a functional catalytic site and, thus, cannot function as a kinase. IRAK-M associates with, and prevents the dissociation of, IRAK–IRAK-4–TNF receptor–associated factor 6 from the TLR signaling complex, with resultant disruption of downstream signaling. Thus, IRAK-M acts as a dominant negative IRAK. We show here that mice that lack IRAK-M develop severe osteoporosis, which is associated with the accelerated differentiation of osteoclasts, an increase in the half-life of osteoclasts, and their activation. Ligation of IL-1R or TLRs results in hyperactivation of NF-κB and mitogen-activated protein kinase signaling pathways, which are essential for osteoclast differentiation. Thus, IRAK-M is a key regulator of the bone loss that is due to osteoclastic resorption of bone

Multinucleation followed by an acytokinetic cell division in myxofibrosarcoma with giant cell proliferation

<p>Abstract</p> <p>Background</p> <p>Multinucleated cells are frequently seen in association with a malignant neoplasm. Some of these multinucleated cells are considered to be neoplastic. The mechanism of neoplastic multinucleation remains unknown, but is considered to be induced by either cell-cell fusion or acytokinetic cell division. Myxofibrosarcoma consists of spindled and pleomorphic tumor cells and bizarre multinucleated giant cells. Some of these multinucleated cells are considered to be neoplastic.</p> <p>Methods</p> <p>We studied the mitotic activity of the multinucleated cells by Ki-67 immunohistochemistry, and the dynamics and differentiation by live-cell video microscopy in the two myxofibrosarcoma cell lines to determine whether the mechanism of multinucleation is cell-cell fusion or acytokinetic cell division</p> <p>Results</p> <p>A Ki-67 immunohistochemical analysis revealed a high positive rate of multinucleated cells, as well as mononuclear cells, and mitotic ability was shown in the multinucleated cells. In live-cell video microscopy, most of the multinucleated cells were induced via the process of acytokinetic cell division.</p> <p>Conclusion</p> <p>The current study indicates that a vulnerability of the cytoskeleton components, such as the contractile ring, causes multinucleation to occur from the telophase to the cytokinesis of the cell cycle.</p

The Problem of Colliding Networks and its Relation to Cancer

Complex systems, ranging from living cells to human societies, can be represented as attractor networks, whose basic property is to exist in one of allowed states, or attractors. We noted that merging two systems that are in distinct attractors creates uncertainty, as the hybrid system cannot assume two attractors at once. As a prototype of this problem, we explore cell fusion, whose ability to combine distinct cells into hybrids was proposed to cause cancer. By simulating cell types as attractors, we find that hybrids are prone to assume spurious attractors, which are emergent and sporadic states of networks, and propose that cell fusion can make a cell cancerous by placing it into normally inaccessible spurious states. We define basic features of hybrid networks and suggest that the problem of colliding networks has general significance in processes represented by attractor networks, including biological, social, and political phenomena

STC1 interference on calcitonin family of receptors signaling during osteoblastogenesis via adenylate cyclase inhibition

Stanniocalcin 1 (STC1) and calcitonin gene-related peptide (CGRP) are involved in bone formation/remodeling. Here we investigate the effects of STC1 on functional heterodimer complex CALCRL/RAMP1, expression and activity during osteoblastogenesis. STC1 did not modify CALCRL and ramp 1 gene expression during osteoblastogenesis when compared to controls. However, plasma membrane spatial distribution of CALCRL/RAMP1 was modified in 7-day pre-osteoblasts exposed to either CGRP or STC1, and both peptides induced CALCRL and RAMP1 assembly. CGRP, but not STC1 stimulated cAMP accumulation in 7-day osteoblasts and in CALCRL/RAMP1 transfected HEK293 cells. Furthermore, STC1 inhibited forskolin stimulated cAMP accumulation of HEK293 cells, but not in CALCRL/RAMP1 transfected HEK293 cells. However, STC1 inhibited cAMP accumulation in calcitonin receptor (CTR) HEK293 transfected cells stimulated by calcitonin. In conclusion, STC1 signals through inhibitory G-protein modulates CGRP receptor spatial localization during osteoblastogenesis and may function as a regulatory factor interacting with calcitonin peptide members during bone formation. (C) 2015 Elsevier Ireland Ltd. All rights reserved.CAPES/CNPq (VS PNPD fellowship program); FAPERGS/CNPq [008/2009 (FCRG)]; Portuguese Foundation for Science and Technology (FCT) [PTDC/MAR/121279/2010, PEst-C/MAR/LA0015/2013, SFRH/BPD/89811/2012]; CNPq (SRT PhD fellowship program); CNPq (LAMM PhD fellowship program); CNPq (FCRG research productivity fellowship program); INCT Exitotoxicity and Neuroprotection (DOGS

Rapid and Sensitive Lentivirus Vector-Based Conditional Gene Expression Assay to Monitor and Quantify Cell Fusion Activity

Cell-to-cell fusion is involved in multiple fundamental biological processes. Prominent examples include osteoclast and giant cell formation, fertilization and skeletal myogenesis which involve macrophage, sperm-egg and myoblast fusion, respectively. Indeed, the importance of cell fusion is underscored by the wide range of homeostatic as well as pathologic processes in which it plays a key role. Therefore, rapid and sensitive systems to trace and measure cell fusion events in various experimental systems are in demand. Here, we introduce a bipartite cell fusion monitoring system based on a genetic switch responsive to the site-specific recombinase FLP. To allow flexible deployment in both dividing as well as non-dividing cell populations, inducer and reporter modules were incorporated in lentivirus vector particles. Moreover, the recombinase-inducible transcription units were designed in such a way as to minimize basal activity and chromosomal position effects in the “off” and “on” states, respectively. The lentivirus vector-based conditional gene expression assay was validated in primary human mesenchymal stem cells and in a differentiation model based on muscle progenitor cells from a Duchenne muscular dystrophy patient using reporter genes compatible with live- and single-cell imaging and with whole population measurements. Using the skeletal muscle cell differentiation model, we showed that the new assay displays low background activity, a 2-log dynamic range, high sensitivity and is amenable to the investigation of cell fusion kinetics. The utility of the bipartite cell fusion monitoring system was underscored by a study on the impact of drug- and RNAi-mediated p38 MAPK inhibition on human myocyte differentiation. Finally, building on the capacity of lentivirus vectors to readily generate transgenic animals the present FLP-inducible system should be adaptable, alone or together with Cre/loxP-based assays, to cell lineage tracing and conditional gene manipulation studies in vivo