Developmental origin and maintenance of distinct testicular macrophage populations

International audienceTesticular macrophages (tM phi) are the principal immune cells of the mammalian testis. Beyond classical immune functions, they have been shown to be important for organogenesis, spermatogenesis, and male hormone production. In the adult testis, two different macrophage populations have been identified based on their distinct tissue localization and morphology, but their developmental origin and mode of homeostatic maintenance are unknown. In this study, we use genetic lineage-tracing models and adoptive transfer protocols to address this question. We show that embryonic progenitors give rise to the interstitial macrophage population, whereas peritubular macrophages are exclusively seeded postnatally in the prepuberty period from bone marrow (BM)-derived progenitors. As the proliferative capacity of interstitial macrophages declines, BM progenitors also contribute to this population. Once established, both the peritubular and interstitial macrophage populations exhibit a long life span and a low turnover in the steady state. Our observations identify distinct developmental pathways for two different tM phi populations that have important implications for the further dissection of their distinct roles in organ homeostasis and testicular function

Characterisation of Genome-Wide PLZF/RARA Target Genes

The PLZF/RARA fusion protein generated by the t(11;17)(q23;q21) translocation in acute promyelocytic leukaemia (APL) is believed to act as an oncogenic transcriptional regulator recruiting epigenetic factors to genes important for its transforming potential. However, molecular mechanisms associated with PLZF/RARA-dependent leukaemogenesis still remain unclear

Les complexes MafB/MaffB et MafB/c-Fos (dualité dans la prolifération)

AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Role of bZip transcription factors MafB and c-Maf in macrophages differenciation

Nous montrons ici que l expression des facteurs de transcription MafB et c-Maf restreint la prolifération des monocytes matures et des macrophages, avec pour conséquence de les conduire au stade terminal de différenciation. En absence de MafB ou de c-Maf, le développement des macrophages est normal. Toutefois, une absence combinée de MafB et de c-Maf (DKO) induit la prolifération des macrophages différenciés en réponse au M-CSF. Ce potentiel prolifératif n est pas restreint aux seuls macrophages dérivés du foie foetal puisque les monocytes triés à partir de sang de souris reconstituées ou les macrophages tissulaires présentent également ce potentiel prolifératif en réponse au M-CSF. La prolifération de ces cellules différenciées est dépendante de Myc et Klf4 mais indépendante de p16 et p19. Enfin, les monocytes DKO triés peuvent être clonés et re-clonés avec une grande efficacité. Bien que les cellules DKO aient la possibilité de proliférer ex vivo, ils conservent leur qualité de macrophages matures et ne sont pas transformés. De plus, lorsqu elles sont injectées dans des souris syngéniques, les cellules DKO sont détectées dans les tissus périphériques. L ensemble de nos résultats suggère que MafB et c-Maf restreignent le potentiel prolifératif des monocytes matures, les rendant post-mitotiques. Nous décrivons donc un rôle nouveau pour MafB et c-Maf dans le contrôle du cylce cellulaire des monocytes matures.We have shown here that expression of MafB and c-Maf restricts the ability of mature monocytes and macrophages to proliferate and lead them to the terminal differentiated state. In absence of MafB or c-Maf macrophages terminal differentiation was unaffected; however, combined deficiency of both MafB and c-Maf led differentiated macrophages to proliferate upon M-CSF stimulation. In addition, this proliferation potential was not restricted to fetal liver derived macrophages as MafB/c-Maf double deficient (DKO) sorted monocytes from peripheral blood of reconstituted mice or tissue macrophages also had potential to proliferate on M-CSF stimulation. Proliferation of terminally differentiated cells was c-Myc and Klf4 dependent, but was independent of p16, and p19. Finally DKO sorted monocytes could be cloned and re-cloned with a high efficiency. Although DKO macrophages have proliferation potential ex vivo, they remain mature macrophages and untransformed. Furthermore, they could be detected in the peripheral tissue of intra venously syngenic mice. Taken together, our data suggest a novel role of MafB and c-Maf in terminal monocytic differentiation by keeping the macrophages out of cell cycle when mitogenic M-CSF stimulus of M-CSF is given.AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Beyond stem cells: self-renewal of differentiated macrophages.

In many mammalian tissues, mature differentiated cells are replaced by self-renewing stem cells, either continuously during homeostasis or in response to challenge and injury. For example, hematopoietic stem cells generate all mature blood cells, including monocytes, which have long been thought to be the major source of tissue macrophages. Recently, however, major macrophage populations were found to be derived from embryonic progenitors and to renew independently of hematopoietic stem cells. This process may not require progenitors, as mature macrophages can proliferate in response to specific stimuli indefinitely and without transformation or loss of functional differentiation. These findings suggest that macrophages are mature differentiated cells that may have a self-renewal potential similar to that of stem cells

Blood monocytes:development, heterogeneity, and relationship with dendritic cells

International audienceMonocytes are circulating blood leukocytes that play important roles in the inflammatory response, which is essential for the innate response to pathogens. But inflammation and monocytes are also involved in the pathogenesis of inflammatory diseases, including atherosclerosis. In adult mice, monocytes originate in the bone marrow in a Csf-1R (MCSF-R, CD115)-dependent manner from a hematopoietic precursor common for monocytes and several subsets of macrophages and dendritic cells (DCs). Monocyte heterogeneity has long been recognized, but in recent years investigators have identified three functional subsets of human monocytes and two subsets of mouse monocytes that exert specific roles in homeostasis and inflammation in vivo, reminiscent of those of the previously described classically and alternatively activated macrophages. Functional characterization of monocytes is in progress in humans and rodents and will provide a better understanding of the pathophysiology of inflammation

Eosinophils and mast cells: a lineage apart

International audienceSingle-cell transcriptome analysis has identified progenitor populations with mast-cell and eosinophil potential that are distinct from the neutrophil-monocyte lineage, segregate early in hematopoietic development and can be discriminated by expression of the transcription factor GATA-1