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Bone marrow-derived non-transformed murine macrophages with an unlimited self-renewing ability

ABSTRACT: Tissue macrophages derive from bone marrow monocytes, and recent studies using mice have revealed that they also derive from yolk sac precursors or fetal liver monocytes. However, embryo-derived macrophages are supposed to be more important to maintain tissue macrophage pool because they can self-renew. Here, we show that adult bone marrow-derived macrophages (MDM) also retain the ability of self-renewal. Where they were readily obtained by a long-term culture: mouse bone marrow cells were cultured with macrophage colony-stimulating factor (M-CSF). After several passages, most MDM died owing to their limited life span with survival and expansion of self-renewing macrophages resided in a small fraction. Self-renewing macrophages were not tumorigenic, but proliferate for a long period in almost unlimited numbers. Despite being distinct from MDM, they were phenotypically and functionally differentiated macrophages, and could differentiate into dendritic cells or osteoclasts. Moreover, Krüppel-like Factor 2 (KLF2) involved in self-renewal of embryonic stem cells, was markedly up-regulated by M-CSF-stimulation in self-renewing macrophages, which was accompanied with a gradual down-regulation of MafB, a suppressor of KLF2 expression. Importantly, knockdown of KLF2 as well as c-Myc caused cell cycle arrest, apoptosis, and diminished cell growth. Our culture method results suggest the presence of precursor(s) for self-renewing macrophages in adult bone marrow that can be used to describe discrepancy of adult- and embryo-derived macrophages. Microarray data from both monocyte-derived and bone marrow-derived mouse macrophages are used to detail the global gene expression profile underlying phenotype, function and self-renewal capacity in order to unravel difference/similarity in phenotype/function and mechanism/degree of self-renewal between the two distinct macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE142619 | GEO | 2019/12/27

REPOSITORIES: GEO

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Project description:The domestic pig (Sus scrofa) provides a large animal model for human innate immune responses and inflammation that is also economically important in its own right. Results: We demonstrate that macrophages can be harvested from 3 different compartments of the pig (lungs, blood and bone-marrow), cryopreserved and subsequently recovered and differentiated in CSF-1. We have performed surface marker analysis and gene expression profiling on macrophages from these compartments, comparing 25 animals from 5 different breeds and their response to lipopolysaccharide. The results provide a clear distinction between alveolar macrophages (AM) and monocyte-derived (MDM) and bone-marrow-derived macrophages (BMDM). In particular, the lung macrophages express the growth factor, Flt1 and its ligand, VEGFA at high levels, suggesting a distinct pathway of growth regulation. We confirm that pig macrophages more closely resemble human, than mouse, in their set of LPS-inducible genes. Relatively few genes showed breed-specific differential expression, notably CXCR2 and CD302 in alveolar macrophages. In contrast, there was substantial inter-individual variation between pigs within breeds, mostly affecting genes annotated as being involved in immune responses. Conclusions: Future research will address whether such variation is heritable, and might form the basis for selective breeding for disease resistance or functional genomics. The domestic pig (Sus scrofa) provides a large animal model for human innate immune responses and inflammation that is also economically important in its own right. We demonstrate that macrophages can be harvested from 3 different compartments of the pig (lungs, blood and bone-marrow), cryopreserved and subsequently recovered and differentiated in CSF-1. We have performed surface marker analysis and gene expression profiling on macrophages from these compartments, comparing 25 animals from 5 different breeds and their response to lipopolysaccharide. The results provide a clear distinction between alveolar macrophages (AM) and monocyte-derived (MDM) and bone-marrow-derived macrophages (BMDM). In particular, the lung macrophages express the growth factor, Flt1 and its ligand, VEGFA at high levels, suggesting a distinct pathway of growth regulation. We confirm that pig macrophages more closely resemble human, than mouse, in their set of LPS-inducible genes. Relatively few genes showed breed-specific differential expression, notably CXCR2 and CD302 in alveolar macrophages. In contrast, there was substantial inter-individual variation between pigs within breeds, mostly affecting genes annotated as being involved in immune responses. Future research will address whether such variation is heritable, and might form the basis for selective breeding for disease resistance or functional genomics. 140 Affymetrix Snowball microarray were analysed from 5 different breed (DR, LR, LW, PIE and HAM). 5 pig per breed were used and cells were harvested from Lungs, blood and bone-marrow (AM, MDM and BMDM). Cells were left untreated (0h) or stimulated with LPS Salmonella enterica serotype minnesota Re 595 - 100ng/ml (7h)

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Bone marrow-derived non-transformed murine macrophages with an unlimited self-renewing ability

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