The development and maintenance of the mononuclear phagocyte system of the chick is controlled by signals from the macrophage colony-stimulating factor receptor.

BACKGROUND: Macrophages have many functions in development and homeostasis as well as innate immunity. Recent studies in mammals suggest that cells arising in the yolk sac give rise to self-renewing macrophage populations that persist in adult tissues. Macrophage proliferation and differentiation is controlled by macrophage colony-stimulating factor (CSF1) and interleukin 34 (IL34), both agonists of the CSF1 receptor (CSF1R). In the current manuscript we describe the origin, function and regulation of macrophages, and the role of CSF1R signaling during embryonic development, using the chick as a model. RESULTS: Based upon RNA-sequencing comparison to bone marrow-derived macrophages grown in CSF1, we show that embryonic macrophages contribute around 2% of the total embryo RNA in day 7 chick embryos, and have similar gene expression profiles to bone marrow-derived macrophages. To explore the origins of embryonic and adult macrophages, we injected Hamburger-Hamilton stage 16 to 17 chick embryos with either yolk sac-derived blood cells, or bone marrow cells from EGFP+ donors. In both cases, the transferred cells gave rise to large numbers of EGFP+ tissue macrophages in the embryo. In the case of the yolk sac, these cells were not retained in hatched birds. Conversely, bone marrow EGFP+ cells gave rise to tissue macrophages in all organs of adult birds, and regenerated CSF1-responsive marrow macrophage progenitors. Surprisingly, they did not contribute to any other hematopoietic lineage. To explore the role of CSF1 further, we injected embryonic or hatchling CSF1R-reporter transgenic birds with a novel chicken CSF1-Fc conjugate. In both cases, the treatment produced a large increase in macrophage numbers in all tissues examined. There were no apparent adverse effects of chicken CSF1-Fc on embryonic or post-hatch development, but there was an unexpected increase in bone density in the treated hatchlings. CONCLUSIONS: The data indicate that the yolk sac is not the major source of macrophages in adult birds, and that there is a macrophage-restricted, self-renewing progenitor cell in bone marrow. CSF1R is demonstrated to be limiting for macrophage development during development in ovo and post-hatch. The chicken provides a novel and tractable model to study the development of the mononuclear phagocyte system and CSF1R signaling.

Dynamic expression of Dab2 in the mouse embryonic central nervous system.

BACKGROUND: Dab2, one of two mammalian orthologs of Drosophila Disabled, has been shown to be involved in cell positioning and formation of visceral endoderm during mouse embryogenesis, but its role in neuronal development is not yet fully understood. In this report, we have examined the localization of the Dab2 protein in the mouse embryonic central nervous system (CNS) at different developmental stages. RESULTS: Dab2 protein was transiently expressed in rhombomeres 5 and 6 of the developing hindbrain between E8.5 and E11.5, and in the floor plate of the neural tube from E9.5 to E12.5, following which it was no longer detectable within these regions. Dab2 protein was also identified within circumventricular organs including the choroid plexus, subcommissural organ and pineal gland during their early development. While Dab2 was still strongly expressed in the adult choroid plexus, immunoreactivity within the subcommissural organ and pineal gland was lost after birth. In addition, Dab2 was transiently expressed within a subpopulation of Iba1-positive mononuclear phagocytes (including presumed microglial progenitors) within the neural tube from E10.0 and was lost by E14.5. Dab2 was separately localized to Iba1 positive cells from E9.5 and subsequently to F4/80 positive cells (mature macrophage/myeloid-derived dendritic cells) positioned outside the neural tube from E12.5 onwards, implicating Dab2 expression in early cells of the mononuclear phagocyte lineage. Dab2 did not co-localize with the pan-neuronal marker PGP9.5 at any developmental stage, suggesting that Dab2 positive cells in the developing CNS are unlikely to be differentiating neurons. CONCLUSION: This is the first study to demonstrate the dynamic spatiotemporal expression of Dab2 protein within the CNS during development.

Ontogeny of S-100 protein-positive histiocytes and lymphocytes in the human fetal lymphoreticular system.

In the human lymphoreticular system, the alpha and beta subunits of S-100 protein are found in ordinary monocyte-macrophages and non-phagocytic histiocytes such as Langerhans cells and interdigitating reticulum cells, respectively. The beta subunit is also present in some CD8+ T cells. In the present study, we investigated the ontogeny of these histiocytes and lymphocytes in humans. Yolk sacs and 4 to 21-week fetuses were examined immunohistochemically for the presence of S-100 protein subunits using antisera monospecific to each subunit. S-100 alpha + macrophages were present in the yolk sacs and the hepatic sinusoids of the 4th week embryos prior to bone marrow hematopoiesis. These macrophages later appeared in other lymphoid organs when anlagen of these organs were formed. No S-100 beta + cells were found in the yolk sacs. S-100 beta+ histiocytes were first detected in the hepatic sinusoids of the 5th week embryo, and after the 8th week of gestation, they were distributed in other lymphoid organs. S-100 beta+ lymphocytes were not found in the liver. They were first detected in the thymus at the 12th week of gestation, and were subsequently distributed in other lymphoid organs. These results suggest that S-100 beta+ lymphocytes and histiocytes may belong to different cell lineages, and the former may not be the precursor of the latter.

Reticulopatías (reticulosis) versus mesenquimopatías sistémicas extraembrionarias: revisión histórica de conceptos. Cánceres mesenquimales (sarcomas) versus tumores sistémicos extraembrionarios / Extraembrionary sistemic mesenchymopathies vs reticulopathies

Se realiza una revisión histórica de la concepción del "Sistema retículo-endotelial" o "sistema retículo-histiocitario" y su aplicación a la patología que generó las llamadas "reticulopatías" y en especial las "reticulosis" (reticulopatías de causa no determinada). Se analiza la naturaleza histológica ultraestructural y embriológica del SRE y se concluye que dicha concepción está basada en erróneas interpretaciones histofisiológicas y embriológicas. El "tejido reticular, que forma el armazón de sostén de los órganos hemocitopoyéticos (bazo, ganglios linfáticoas, médula ósea parda) representa simplemente una variedad de tejido conectivo especializado asociado a un armazón extracelular de fibrillas de reticulina constituidas como las fibras colágenas por proteínas colágenas. Los estudios ultraestructurales de las "células reticulares" no han logrado mostrar evidencias de actividad macrofágica y han permitido observar formas transicionales al fibroblasto. También se ha podido demostrar la imposibilidad de que la "célula reticular" se pueda transformar en "histiocito" o "macrófago". Por otro lado, los "sinusoides" del bazo y del hígado están constituídos por verdaderos endotelios fenestrados, sin vinculación con las células reticulares. Las células de Kupffer del hígado son macrófagos originados en hemocitoblastos (células troncales hemáticas del mesénquima extraembrionario), que viven en los intersticios de los endotelios fenestrados, sin tener vinculaciones citogenéticas con los endotelios sinusoidales. Estos hallazgos han determinado que no se puede seguir admitiendo una función de "mesénquima persistente" para las células reticulares y menos que dichas células puedan generar linfocitos, histiocitos y otras células vinculadas con las que constituyen las reticulosis. La revisión embriológica permite demostrar la existencia de dos mesénquimas, uno más primitivo desarrollado en la pared del saco vitelino, el "mesénquima extraembrionario" y otro posterior, generado en la lámina intermedia del disco embrionario, el "mesénquima embrionario". El "mesénquima extraembrionario" constituirá el real origen de las células que constituyen las llamadas reticulosis. Por dicho motivo se propone reemplazar la denominación "reticulosis" por la más correcta de "mesenquimopatías extraembrionarias sistémicas". Por otra parte, el "mesénquima del disco embrionario" o "mesénquima embrionario" generarías los "sarcomas", es decir tumores mesenquimales circunscriptos que se diseminan

Reticulopatías (reticulosis) versus mesenquimopatías sistémicas extraembrionarias: revisión histórica de conceptos. Cánceres mesenquimales (sarcomas) versus tumores sistémicos extraembrionarios / Extraembrionary sistemic mesenchymopathies vs reticulopathies

Se realiza una revisión histórica de la concepción del "Sistema retículo-endotelial" o "sistema retículo-histiocitario" y su aplicación a la patología que generó las llamadas "reticulopatías" y en especial las "reticulosis" (reticulopatías de causa no determinada). Se analiza la naturaleza histológica ultraestructural y embriológica del SRE y se concluye que dicha concepción está basada en erróneas interpretaciones histofisiológicas y embriológicas. El "tejido reticular, que forma el armazón de sostén de los órganos hemocitopoyéticos (bazo, ganglios linfáticoas, médula ósea parda) representa simplemente una variedad de tejido conectivo especializado asociado a un armazón extracelular de fibrillas de reticulina constituidas como las fibras colágenas por proteínas colágenas. Los estudios ultraestructurales de las "células reticulares" no han logrado mostrar evidencias de actividad macrofágica y han permitido observar formas transicionales al fibroblasto. También se ha podido demostrar la imposibilidad de que la "célula reticular" se pueda transformar en "histiocito" o "macrófago". Por otro lado, los "sinusoides" del bazo y del hígado están constituídos por verdaderos endotelios fenestrados, sin vinculación con las células reticulares. Las células de Kupffer del hígado son macrófagos originados en hemocitoblastos (células troncales hemáticas del mesénquima extraembrionario), que viven en los intersticios de los endotelios fenestrados, sin tener vinculaciones citogenéticas con los endotelios sinusoidales. Estos hallazgos han determinado que no se puede seguir admitiendo una función de "mesénquima persistente" para las células reticulares y menos que dichas células puedan generar linfocitos, histiocitos y otras células vinculadas con las que constituyen las reticulosis. La revisión embriológica permite demostrar la existencia de dos mesénquimas, uno más primitivo desarrollado en la pared del saco vitelino, el "mesénquima extraembrionario" y otro posterior, generado en la lámina intermedia del disco embrionario, el "mesénquima embrionario". El "mesénquima extraembrionario" constituirá el real origen de las células que constituyen las llamadas reticulosis. Por dicho motivo se propone reemplazar la denominación "reticulosis" por la más correcta de "mesenquimopatías extraembrionarias sistémicas". Por otra parte, el "mesénquima del disco embrionario" o "mesénquima embrionario" generarías los "sarcomas", es decir tumores mesenquimales circunscriptos que se diseminan

Development of immune competence.

Present evidence indicates that the precursors of B- and T-cells can be found in the extra-embryonic tissues four days after implantation (day 5) and that by the following day (day 10) certain of the B-cell precursors have differentiated to the stage of the antigen-binding cell. Cells able to secrete antibody are not detected, however, until the later stages of pregnancy. B-cell differentiation has been shown to advance in a stepwise manner through several compartments, and the early stages of maturation are independent of thymic or T-cell regulation. The thymic rudiment appears by the 12th day of pregnancy and the reticuloepithelial tissue is quickly colonized by T-stem cells which migrate from the fetal liver. Within 4 days these cells respond to PHA, recognize and respond to allogeneic antigens, and begin to seed to the peripheral lymphoid tissues. During the latter stages of pregnancy and until about the sixth week after birth T-cell mediated suppressor activity predominates. T-cell killer function can be detected in the neonatal thymus shortly after birth, but this activity increases slowly in the peripheral lymphoid tissues. T-cell helper activity increases slowly after birth as suppressor activity declines. The adult levels of helper-suppressor function are approached about six to eight weeks after birth.