CSF1R-dependent macrophages control postnatal somatic growth and organ maturation.
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...
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Public Library of Science (PLoS)
2021-06-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1009605&type=printable |
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| author | Sahar Keshvari Melanie Caruso Ngari Teakle Lena Batoon Anuj Sehgal Omkar L Patkar Michelle Ferrari-Cestari Cameron E Snell Chen Chen Alex Stevenson Felicity M Davis Stephen J Bush Clare Pridans Kim M Summers Allison R Pettit Katharine M Irvine David A Hume |
| author_facet | Sahar Keshvari Melanie Caruso Ngari Teakle Lena Batoon Anuj Sehgal Omkar L Patkar Michelle Ferrari-Cestari Cameron E Snell Chen Chen Alex Stevenson Felicity M Davis Stephen J Bush Clare Pridans Kim M Summers Allison R Pettit Katharine M Irvine David A Hume |
| author_sort | Sahar Keshvari |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b07f6c8ea0a64f72b0ae56fc9ec6c019 |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2021-06-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj-art-b07f6c8ea0a64f72b0ae56fc9ec6c0192025-08-20T02:23:18ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042021-06-01176e100960510.1371/journal.pgen.1009605CSF1R-dependent macrophages control postnatal somatic growth and organ maturation.Sahar KeshvariMelanie CarusoNgari TeakleLena BatoonAnuj SehgalOmkar L PatkarMichelle Ferrari-CestariCameron E SnellChen ChenAlex StevensonFelicity M DavisStephen J BushClare PridansKim M SummersAllison R PettitKatharine M IrvineDavid A HumeHomozygous 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1009605&type=printable |
| spellingShingle | Sahar Keshvari Melanie Caruso Ngari Teakle Lena Batoon Anuj Sehgal Omkar L Patkar Michelle Ferrari-Cestari Cameron E Snell Chen Chen Alex Stevenson Felicity M Davis Stephen J Bush Clare Pridans Kim M Summers Allison R Pettit Katharine M Irvine David A Hume CSF1R-dependent macrophages control postnatal somatic growth and organ maturation. PLoS Genetics |
| title | CSF1R-dependent macrophages control postnatal somatic growth and organ maturation. |
| title_full | CSF1R-dependent macrophages control postnatal somatic growth and organ maturation. |
| title_fullStr | CSF1R-dependent macrophages control postnatal somatic growth and organ maturation. |
| title_full_unstemmed | CSF1R-dependent macrophages control postnatal somatic growth and organ maturation. |
| title_short | CSF1R-dependent macrophages control postnatal somatic growth and organ maturation. |
| title_sort | csf1r dependent macrophages control postnatal somatic growth and organ maturation |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1009605&type=printable |
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