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Keshvari, Sahar; Caruso, Melanie; Teakle, Ngari; Batoon, Lena; Sehgal, Anuj; Patkar, Omkar L.; Ferrari-Cestari, Michelle; Snell, Cameron E.; Chen, Chen; Stevenson, Alex; Davis, Felicity M.; Bush, Stephen J.; Pridans, Clare; Summers, Kim M.; Pettit, Allison R.; Irvine, Katharine M.; Hume, David A.

CSF1R-dependent macrophages control postnatal somatic growth and organ maturation

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  • Media type: E-Article
  • Title: CSF1R-dependent macrophages control postnatal somatic growth and organ maturation
  • Contributor: Keshvari, Sahar; Caruso, Melanie; Teakle, Ngari; Batoon, Lena; Sehgal, Anuj; Patkar, Omkar L.; Ferrari-Cestari, Michelle; Snell, Cameron E.; Chen, Chen; Stevenson, Alex; Davis, Felicity M.; Bush, Stephen J.; Pridans, Clare; Summers, Kim M.; Pettit, Allison R.; Irvine, Katharine M.; Hume, David A.
  • Published: Public Library of Science (PLoS), 2021
  • Published in: PLOS Genetics, 17 (2021) 6, Seite e1009605
  • Language: English
  • DOI: 10.1371/journal.pgen.1009605
  • ISSN: 1553-7404
  • Origination:
  • Footnote:
  • Description: <jats:p>Homozygous mutation of the <jats:italic>Csf1r</jats:italic> locus (<jats:italic>Csf1rko</jats:italic>) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of <jats:italic>Csf1r</jats:italic> mutation, we bred a rat <jats:italic>Csf1rko</jats:italic> allele to the inbred dark agouti (DA) genetic background and to a <jats:italic>Csf1r</jats:italic>-mApple reporter transgene. The <jats:italic>Csf1rko</jats:italic> led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the <jats:italic>Csf1rko</jats:italic> 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 <jats:italic>Csf1rko</jats:italic> 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 <jats:italic>Csf1rko</jats:italic> rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver <jats:italic>Csf1rko</jats:italic> 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. <jats:italic>Csf1rko</jats:italic> rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43<jats:sup>hi</jats:sup> non-classical monocytes, absent in the <jats:italic>Csf1rko</jats:italic>, were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the <jats:italic>Csf1rko</jats:italic> 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.</jats:p>
  • Access State: Open Access