The Mononuclear Phagocyte System of the Rat

Hume, David; Caruso, Melanie; Keshvari, Sahar; Patkar, Omkar L.; Sehgal, Anuj; Bush, Stephen J.; Summers, Kim M.; Pridans, Clare; Irvine, Katharine M.

doi:10.4049/jimmunol.2100136

Cited by 16 publications

(12 citation statements)

References 194 publications

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“…Baghdadi et al [ 94 ] presented evidence that IL34 production by multiple myeloma cells contributes to tumor-associated osteolysis. In the rat, homozygous Csf1r mutation has a much more profound effect on somatic growth than Csf1 mutation, implying a role for Il34 [ 13 ], but both Csf1 and Csf1r mutants are entirely OCL-deficient. Unlike op/op mice, Csf1 tl/tl rats show no evidence of age-dependent recovery of OCL [ 3 ], and indeed, there is no evidence of extramedullary hematopoiesis in the spleen.…”

Section: Csf1r Signals In Bone Developmentmentioning

confidence: 99%

“…The rather more severe phenotype of the receptor mutation in mice and the age-dependent correction in CSF1-deficient models likely reflect the contribution of a second ligand, interleukin 34 (IL34), which binds to an overlapping site on the receptor and can complement CSF1 deficiency when expressed as a transgene [ 12 ]. By contrast, mutation of Csf1 in the toothless ( tl/tl ) rat is associated with unremitting osteopetrosis and OCL deficiency but a much less severe effect on postnatal somatic growth than in mice [ 3 , 13 ]. The importance of species differences is discussed further below.…”

Section: Introductionmentioning

confidence: 99%

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CSF1R as a Therapeutic Target in Bone Diseases: Obvious but Not so Simple

Hume

Batoon

Sehgal

et al. 2022

Curr Osteoporos Rep

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Purpose of Review The purpose of the review is to summarize the expression and function of CSF1R and its ligands in bone homeostasis and constraints on therapeutic targeting of this axis. Recent Findings Bone development and homeostasis depends upon interactions between mesenchymal cells and cells of the mononuclear phagocyte lineage (MPS), macrophages, and osteoclasts (OCL). The homeostatic interaction is mediated in part by the systemic and local production of growth factors, macrophage colony-stimulating factor (CSF1), and interleukin 34 (IL34) that interact with a receptor (CSF1R) expressed exclusively by MPS cells and their progenitors. Loss-of-function mutations in CSF1 or CSF1R lead to loss of OCL and macrophages and dysregulation of postnatal bone development. MPS cells continuously degrade CSF1R ligands via receptor-mediated endocytosis. As a consequence, any local or systemic increase or decrease in macrophage or OCL abundance is rapidly reversible. Summary In principle, both CSF1R agonists and antagonists have potential in bone regenerative medicine but their evaluation in disease models and therapeutic application needs to carefully consider the intrinsic feedback control of MPS biology.

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Section: Csf1r Signals In Bone Developmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CSF1R as a Therapeutic Target in Bone Diseases: Obvious but Not so Simple

Hume

Batoon

Sehgal

et al. 2022

Curr Osteoporos Rep

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“…Patients present with abnormal skeletal development and calcification, ventricular enlargement (hydrocephalus) and selective loss of microglia in the brain leading to degenerative encephalopathy and brain malformations [8][9][10][11]. Although utility is compromised by the comparative lack of reagents, the rat has many advantages over the mouse for the study of development, physiology, pathology and mononuclear phagocyte homeostasis (reviewed in [12]). We previously generated and characterised Csf1rko rats as an alternative model of human CSF1R deficiency [13].…”

Section: Introductionmentioning

confidence: 99%

CSF1R-dependent macrophages control postnatal somatic growth and organ maturation

et al. 2021

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Homozygous mutation of the Csf1r locus (Csf1rko) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of Csf1r mutation, we bred a rat Csf1rko allele to the inbred dark agouti (DA) genetic background and to a Csf1r-mApple reporter transgene. The Csf1rko led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the Csf1rko phenotype to early postnatal development to reveal impacts on musculoskeletal development and proliferation and morphogenesis in multiple organs. Expression profiling of 3-week old wild-type (WT) and Csf1rko livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and the IGF1/IGF binding protein system. Older Csf1rko rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver Csf1rko rats had greatly-reduced circulating IGF1. Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility. WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency. Csf1rko rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43hi non-classical monocytes, absent in the Csf1rko, were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the Csf1rko phenotype is autonomous to BM-derived cells and indicate that BM contains a progenitor of tissue macrophages distinct from hematopoietic stem cells. The model provides a unique system in which to define the pathways of development of resident tissue macrophages and their local and systemic roles in growth and organ maturation.

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“…The transcriptome of rat macrophages has been analysed previously based upon microarrays ( 67 ) and the RNA-seq data included here ( 68 ). Macrophages adapt to perform specific functions in specific tissues ( 20 ).…”

Section: Resultsmentioning

confidence: 99%

“…In mice and rats, mutation of the Csf1 gene leads to a global reduction in many tissue macrophage populations, whereas mutation of Il34 in mice leads to selective reduction of microglia and Langerhans cells. Based upon the difference in phenotype between Csf1 and Csf1r mutations in rats, we speculated that Il34 could be more widely expressed and functional in rat macrophage homeostasis compared to mouse ( 68 ). Neither growth factor forms part of a cluster.…”

Section: Resultsmentioning

confidence: 99%

Generation and network analysis of an RNA-seq transcriptional atlas for the rat

Summers

Bush

et al. 2022

NAR Genomics and Bioinformatics

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The laboratory rat is an important model for biomedical research. To generate a comprehensive rat transcriptomic atlas, we curated and downloaded 7700 rat RNA-seq datasets from public repositories, downsampled them to a common depth and quantified expression. Data from 585 rat tissues and cells, averaged from each BioProject, can be visualized and queried at http://biogps.org/ratatlas. Gene co-expression network (GCN) analysis revealed clusters of transcripts that were tissue or cell type restricted and contained transcription factors implicated in lineage determination. Other clusters were enriched for transcripts associated with biological processes. Many of these clusters overlap with previous data from analysis of other species, while some (e.g. expressed specifically in immune cells, retina/pineal gland, pituitary and germ cells) are unique to these data. GCN analysis on large subsets of the data related specifically to liver, nervous system, kidney, musculoskeletal system and cardiovascular system enabled deconvolution of cell type-specific signatures. The approach is extensible and the dataset can be used as a point of reference from which to analyse the transcriptomes of cell types and tissues that have not yet been sampled. Sets of strictly co-expressed transcripts provide a resource for critical interpretation of single-cell RNA-seq data.

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The Mononuclear Phagocyte System of the Rat

Cited by 16 publications

References 194 publications

CSF1R as a Therapeutic Target in Bone Diseases: Obvious but Not so Simple

CSF1R as a Therapeutic Target in Bone Diseases: Obvious but Not so Simple

CSF1R-dependent macrophages control postnatal somatic growth and organ maturation

Generation and network analysis of an RNA-seq transcriptional atlas for the rat

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