Abstract
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.
Highlights
Resident macrophages are abundant in every tissue in the body and adapt to each tissue environment by expressing unique gene sets required for their local functions
Monocytes and macrophages are cells of the innate immune system produced by the bone marrow that can be recruited into tissues to support defense against infection and repair following injury
-called resident macrophages are abundant in every tissue in the body
Summary
Resident macrophages are abundant in every tissue in the body and adapt to each tissue environment by expressing unique gene sets required for their local functions (reviewed in [1,2]) Their differentiation from progenitor cells, their gene expression profile and their survival/ maintenance in tissues is controlled by two ligands, colony stimulating factor 1 (CSF1) and interleukin 34 (IL34), which each signal through the CSF1 receptor (CSF1R) (reviewed in [3]). We previously generated and characterised Csf1rko rats as an alternative model of human CSF1R deficiency [13] This model was initially established and analysed on a mixed genetic background to avoid the pre-weaning mortality seen in Csf1rko mice. To enable us to test complementation of the Csf1rko mutation by transfer of bone marrow (BM) and to establish a more consistent model
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
