Transcriptional profiling of young and old mouse macrophages interacting with nanoparticles [Bulk RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205826 | GEO | 2023/07/18
REPOSITORIES: GEO
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Project description:The mononuclear phagocytic system is integral to the clearance of nanotherapeutics. However, the precise mechanisms involved in the phagocytic clearance of nanotherapeutics, and how age-associated changes in innate immune cells affect this clearance, are poorly understood. We found that the ability of professional phagocytes to take up nanoparticles diminishes with age. Bulk RNA sequencing of bone marrow derived macrophages and single cell RNA sequencing of liver macrophages derived from young and old mice was carried out to investigate the gene expression changes that may be assiciated with the changed ability of macrophages to uptake nanoparticles.
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Project description:This SuperSeries is composed of the SubSeries listed below.Nanomedicines have been approved to treat multiple human diseases. However, clinical adoption of nanoformulated agents is often hindered by concerns about hepatic uptake and clearance, a process that is not fully understood. Here we show that the antitumour efficacy of cancer nanomedicine exhibits an age-associated disparity. Tumour delivery and treatment outcomes are superior in old versus young mice, probably due to an age-related decline in the ability of hepatic phagocytes to take up and remove nanoparticles. Transcriptomic- and protein-level analysis at the single-cell and bulk levels reveals an age-associated decrease in the numbers of hepatic macrophages that express the scavenger receptor MARCO in mice, non-human primates and humans. Therapeutic blockade of MARCO is shown to decrease the phagocytic uptake of nanoparticles and improve the antitumour effect of clinically approved cancer nanotherapeutics in young but not aged mice. Together, these results reveal an age-associated disparity in the phagocytic clearance of nanotherapeutics that affects their antitumour response, thus providing a strong rationale for an age-appropriate approach to cancer nanomedicine.
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Project description:Macrophages and dendritic cells have long been appreciated for their ability to migrate to and engulf dying cells and debris, including some of the billions of cells that are naturally eliminated from our body daily. However, a substantial amount of these dying cells are cleared by local tissue cells, so-called ‘non-professional phagocytes’, critical to preserve organismal fitness. How non-professional phagocytes are able to sense and digest nearby apoptotic corpses while still performing their normal tissue functions is unclear. Here, we explore the molecular mechanisms underlying this balancing act. Exploiting the cyclical bouts of tissue regeneration and degeneration during the hair cycle, we show that stem cells can transiently become non-professional phagocytes when confronted with dying cells. Adoption of this phagocytic state requires not only local lipids produced by apoptotic corpses, which are necessary for RXRα activation, but also tissue-specific retinoids able to activate RARg. The dual factor dependency enables tight regulation of the genes requisite to activate phagocytic apoptotic clearance. The tunable phagocytic program we describe here offers an attractive mechanism to offset phagocytic duties against the primary stem cell function of replenishing differentiated cells to preserve tissue integrity during homeostasis. Our findings have broad implications for other non-motile stem or progenitor cells which experience cell death in an immune-privileged niche.
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Project description:Macrophages and dendritic cells have long been appreciated for their ability to migrate to and engulf dying cells and debris, including some of the billions of cells that are naturally eliminated from our body daily. However, a substantial amount of these dying cells are cleared by local tissue cells, so-called ‘non-professional phagocytes’, critical to preserve organismal fitness. How non-professional phagocytes are able to sense and digest nearby apoptotic corpses while still performing their normal tissue functions is unclear. Here, we explore the molecular mechanisms underlying this balancing act. Exploiting the cyclical bouts of tissue regeneration and degeneration during the hair cycle, we show that stem cells can transiently become non-professional phagocytes when confronted with dying cells. Adoption of this phagocytic state requires not only local lipids produced by apoptotic corpses, which are necessary for RXRα activation, but also tissue-specific retinoids able to activate RARg. The dual factor dependency enables tight regulation of the genes requisite to activate phagocytic apoptotic clearance. The tunable phagocytic program we describe here offers an attractive mechanism to offset phagocytic duties against the primary stem cell function of replenishing differentiated cells to preserve tissue integrity during homeostasis. Our findings have broad implications for other non-motile stem or progenitor cells which experience cell death in an immune-privileged niche.
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Project description:Macrophages and dendritic cells have long been appreciated for their ability to migrate to and engulf dying cells and debris, including some of the billions of cells that are naturally eliminated from our body daily. However, a substantial amount of these dying cells are cleared by local tissue cells, so-called ‘non-professional phagocytes’, critical to preserve organismal fitness. How non-professional phagocytes are able to sense and digest nearby apoptotic corpses while still performing their normal tissue functions is unclear. Here, we explore the molecular mechanisms underlying this balancing act. Exploiting the cyclical bouts of tissue regeneration and degeneration during the hair cycle, we show that stem cells can transiently become non-professional phagocytes when confronted with dying cells. Adoption of this phagocytic state requires not only local lipids produced by apoptotic corpses, which are necessary for RXRα activation, but also tissue-specific retinoids able to activate RARg. The dual factor dependency enables tight regulation of the genes requisite to activate phagocytic apoptotic clearance. The tunable phagocytic program we describe here offers an attractive mechanism to offset phagocytic duties against the primary stem cell function of replenishing differentiated cells to preserve tissue integrity during homeostasis. Our findings have broad implications for other non-motile stem or progenitor cells which experience cell death in an immune-privileged niche.
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