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Gene therapy of Csf2ra-/- deficiency in long-term cultured fetal monocyte precursors restores bona fide alveolar macrophage development and function in mice

ABSTRACT: Tissue-resident macrophage-based immune therapies have been proposed for various diseases. However, generation of sufficient numbers that possess tissue-specific functions remains a major handicap. Here, we show that fetal liver monocytes cultured with GM-CSF (CSF2-cFLiMo) rapidly differentiate into a long-lived, homogeneous alveolar macrophage (AM)-like population in vitro. CSF2-cFLiMo remained the capacity to develop into bona fide AM upon transfer into Csf2ra-/- neonates and prevented development of alveolar proteinosis and accumulation of apoptotic cells for at least 1 year in vivo. CSF2-cFLiMo more efficiently engrafted empty AM niches in the lung and protected mice from severe pathology induced by respiratory viral infection, compared to transplantation of macrophages derived from bone marrow cells cultured with M-CSF (CSF1-cBMM) in the presence or absence of GM-CSF. Harnessing the potential of this approach for gene therapy, we restored a disrupted Csf2ra gene in FLiMo and demonstrated their capacity to develop into AM in vivo. Together, we provide a novel platform for generation of immature AM-like precursors amenable for genetic manipulation, which will be useful to dissect AM development and function and pulmonary transplantation therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE193537 | GEO | 2022/01/15

REPOSITORIES: GEO

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Project description:GM-CSF receptor-β deficient (Csf2rb–/– or KO) mice develop a lung disease identical to hereditary pulmonary alveolar proteinosis (hPAP) in humans with recessive CSF2RA or CSF2RB mutations that impair GM-CSF receptor function. We performed pulmonary macrophage transplantation (PMT) of bone marrow derived macrophages (BMDMs) without myeloablation in Csf2rb–/–mice. BMDMs were administered by endotracheal instillation into 2 month-old Csf2rb–/– mice. Results demonstrated that PMT therapeutic of hPAP in Csf2rb–/– mice was highly efficacious and durable. Alveolar macrophages were isolated by bronchoalveolar lavage one year after administration subjected to microarray analysis to determine the effects of PMT therapy on the global gene expression profile.

2014-10-01 | GSE60528 | GEO

Project description:GM-CSF receptor-Î² deficient (Csf2rbâ/â or KO) mice develop a lung disease identical to hereditary pulmonary alveolar proteinosis (hPAP) in humans with recessive CSF2RA or CSF2RB mutations that impair GM-CSF receptor function. We performed pulmonary macrophage transplantation (PMT) of bone marrow derived macrophages (BMDMs) without myeloablation in Csf2rbâ/âmice. BMDMs were administered by endotracheal instillation into 2 month-old Csf2rbâ/â mice. Results demonstrated that PMT therapeutic of hPAP in Csf2rbâ/â mice was highly efficacious and durable. Alveolar macrophages were isolated by bronchoalveolar lavage one year after administration subjected to microarray analysis to determine the effects of PMT therapy on the global gene expression profile. Total mRNA was isolated from alveolar macrophages PMT-treated Csf2rbâ/âmice (PMT) and from age-matched, untreated KO mice (KO) and wild-type (C57Bl/6) mice (WT). Total mRNA was evaluated using Affymetrix microarrays (Mouse Gene 1.0 ST Array) to compare the gene expression profiles among the three groups (3 mice/group).

2014-10-01 | E-GEOD-60528 | biostudies-arrayexpress

Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function.

Project description:Pulmonary alveolar proteinosis (PAP) results from a dysfunction of alveolar macrophages (AMs), chiefly due to disruptions in the signaling of granulocyte macrophage colony-stimulating factor (GM-CSF). We found that mice deficient for the B lymphoid transcription repressor BTB and CNC homology 2 (Bach2) developed PAP-like accumulation of surfactant proteins in the lungs. Bach2 was expressed in AMs, and Bach2-deficient AMs showed alterations in lipid handling in comparison with wild-type (WT) cells. Although Bach2-deficient AMs showed a normal expression of the genes involved in the GM-CSF signaling, they showed an altered expression of the genes involved in chemotaxis, lipid metabolism, and alternative M2 macrophage activation with increased expression of Ym1 and arginase-1, and the M2 regulator Irf4. Peritoneal Bach2-deficient macrophages showed increased Ym1 expression when stimulated with interleukin-4. More eosinophils were present in the lung and peritoneal cavity of Bach2-deficient mice compared with WT mice. The PAP-like lesions in Bach2-deficient mice were relieved by WT bone marrow transplantation even after their development, confirming the hematopoietic origin of the lesions. These results indicate that Bach2 is required for the functional maturation of AMs and pulmonary homeostasis, independently of the GM-CSF signaling. WT (n=8) and Bach2KO (n=3) AMs. One expreriment was performed.

2014-01-15 | E-GEOD-54050 | biostudies-arrayexpress

Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function.

2014-01-15 | GSE54050 | GEO

Fetal monocytes possess increased metabolic capacity and replace primitive macrophages in tissue macrophage development

Project description:We studied alveolar macrophage (AM) development after single and competitive transplantation of different precursors from YS, fetal liver, and lung into neonatal Csf2ra-/- mice, which lack endogenous AM. Fetal monocytes, promoted by Myb, outcompeted primitive MΦ (pMΦ) in empty AM niches and preferentially developed to mature AM, which is associated with enhanced mitochondrial respiratory and glycolytic capacity and repression of the transcription factors c-Maf and MafB. Interestingly, AM derived from pMΦ failed to efficiently clear alveolar proteinosis and protect from fatal lung failure following influenza virus infection. Thus, our data demonstrate superior developmental and functional capacity of fetal monocytes over pMΦ in AM development and underlying mechanisms explaining replacement of pMΦ in fetal tissues.

2019-12-30 | GSE140645 | GEO

MICEPAP Trial

Project description:<p>The purpose of this study is to (1) compare a technically improved assay with an existing assay used to measure serum anti-GM-CSF antibodies in stored serum samples previously obtained from patients diagnosed with either primary, secondary, congenital or idiopathic pulmonary alveolar proteinosis (PAP), other chronic diseases or disease-free, healthy individuals; (2) determine the prevalence and levels of anti-GM-CSF autoantibodies and (3) define the breadth of the autoimmune antibody responses in primary PAP patients from the United States, Japan, Australia, and Europe using previously collected serum samples; and (4) using a chart review approach, compare the clinical, radiologic and laboratory features of primary PAP patients to determine if differences exist among patients in these globally geographically distributed regions.</p>

| phs001309 | dbGaP

Sca1+ macrophages activate hematopoietic stem/progenitor cells upon bone marrow stress. [scRNA-Seq]

Project description:Although hematopoietic stem and progenitor cells (HSPCs) become activated in the cell-cycle status after chemotherapy to supply hematopoietic loss, the detailed mechanisms of activation remain unknown. Here we show that Sca1+ macrophages play a key role for bone marrow (BM) recovery through granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. By analyzing gene expression profiles of HSPCs lodged in 5-fluolouracil (5-FU)-treated mice, we found GM-CSF as a key proliferative signal. Sca1+ macrophages in BM after 5-FU treatment expressed high levels of GM-CSF. GM-CSF-knockout mice treated with 5-FU were lethal because of severe BM suppression. Up-regulation of Csf2 in Sca1+ macrophages by 5-FU was suppressed in MyD88-knockout mice, suggesting that TLR signaling via damage-associated molecular patterns caused by cell death is critical for up-regulation of Csf2. In 5-FU treated BM, majority of Sca1+ macrophages and transplanted HSPCs locate perivascular areas. These findings together indicate that Sca1+ macrophages induce HSPCs to proliferate through GM-CSF signaling in the stressed BM environments.

2021-01-20 | GSE120112 | GEO

Sca1+ macrophages activate hematopoietic stem/progenitor cells upon bone marrow stress. [RNA-Seq]

2021-01-20 | GSE120111 | GEO

Cish attenuates homeostatic cytokine signaling to promote lung-specific macrophage programming and function

Project description:Lung-specific expression of the SOCS family member Cish is driven by steady-state GM-CSF signaling and shapes alveolar macrophage identity and homeostatic function.

2021-08-26 | GSE156967 | GEO

Pathogenic Mutation that Dislocates GATA2 Zinc Fingers Establishes a Hematopoiesis-Disrupting Signaling Network

Project description:While certain human genetic variants are conspicuously loss-of-function, decoding the functional impact of many variants is challenging. Previously, we described a leukemia predisposition syndrome (GATA2-deficiency) patient with a germline GATA2 variant that inserts nine amino acids between the two zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies in Gata2 enhancer-mutant hematopoietic progenitor cells to reveal how the insertion impacts GATA2 function genome-wide. Despite being nuclear-localized, 9aa-Ins was severely defective, with activation more impaired than repression. Variation of the inter-zinc finger spacer length revealed that repression tolerated insertions that were detrimental to activation. GATA2 deficiency generated a hematopoiesis-disrupting signaling network in progenitor cells with reduced Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) signaling and elevated Interleukin-6 (IL-6) signaling. As insufficient GM-CSF signaling causes pulmonary alveolar proteinosis and excessive IL-6 signaling causes bone marrow failure, hallmark phenotypes of GATA2-deficiency patients, these results establish molecular mechanisms underlying GATA2-linked pathologies.

2023-02-22 | GSE201968 | GEO

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