Resident Macrophages Reprogram Toward a Developmental State After Acute Kidney Injury
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA497279 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8071920_1.fastq.gz | Fastqsanger.gz | |||
| SRR8071920_2.fastq.gz | Fastqsanger.gz | |||
| SRR8071911_1.fastq.gz | Fastqsanger.gz | |||
| SRR8071911_2.fastq.gz | Fastqsanger.gz | |||
| SRR8071921_1.fastq.gz | Fastqsanger.gz |
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Project description:Background – Acute kidney injury (AKI) is a devastating clinical condition affecting at least two-thirds of critically ill patients and among these patients is associated with a greater than 60% risk of mortality. Kidney mononuclear phagocytes (MP) are necessary for pathogenesis and healing in mouse models of AKI and thus have been the subject of investigation as potential targets for clinical interventions. Methods and Results – We have determined that, after injury, F4/80Hi-expressing kidney resident macrophages (KRM) are a distinct cellular subpopulation that does not differentiate from non-resident infiltrating MP. However, if KRM are depleted using polyinosinic:polycytidylic acid (poly I:C), they can be reconstituted from bone marrow derived precursors. Further, KRM lack major histocompatibility complex class II (MHCII) expression before post-parturition day 7 (P7) but upregulate it over the next 14 days. This MHCII- KRM phenotype reappears after injury. RNA sequencing shows injury causes transcriptional reprogramming of KRM to more closely resemble that found at P7. Post-injury KRM are also enriched in Wingless-type MMTV integration site family (Wnt) signaling, indicating a pathway vital for mouse and human kidney development is active. Conclusions – These data indicate that mechanisms involved in kidney development may be active after injury in KRM.
2019-04-16 | GSE121410 | GEO
Project description:Acute kidney injury (AKI) is a devastating clinical condition affecting at least two-thirds of critically ill patients, and, among these patients, it is associated with a greater than 60% risk of mortality. Kidney mononuclear phagocytes (MPs) are implicated in pathogenesis and healing in mouse models of AKI and, thus, have been the subject of investigation as potential targets for clinical intervention. We have determined that, after injury, F4/80hi-expressing kidney-resident macrophages (KRMs) are a distinct cellular subpopulation that does not differentiate from nonresident infiltrating MPs. However, if KRMs are depleted using polyinosinic/polycytidylic acid (poly I:C), they can be reconstituted from bone marrow-derived precursors. Further, KRMs lack major histocompatibility complex class II (MHCII) expression before P7 but upregulate it over the next 14 days. This MHCII- KRM phenotype reappears after injury. RNA sequencing shows that injury causes transcriptional reprogramming of KRMs such that they more closely resemble that found at P7. KRMs after injury are also enriched in Wingless-type MMTV integration site family (Wnt) signaling, indicating that a pathway vital for mouse and human kidney development is active. These data indicate that mechanisms involved in kidney development may be functioning after injury in KRMs.
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Project description:To obtain an unbiased characterization of the resident and infiltrating immune cell populations of mouse kidneys in healthy and diseased states, we performed single cell RNA-seq of facs-sorted CD45+ immune cells and CD4+ T cells from naïve and injured kidneys, at selected time points.
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Project description:Acute kidney injury (AKI) is a major health burden in the United States. Macrophages have been shown to mediate AKI in murine models. Murine kidneys contain multiple subpopulations of kidney resident macrophages (KRM) that are transcriptionally and spatially distinct. We hypothesized the human kidney contains orthologous KRM subpopulations, both transcriptionally and spatially. We utilized kidney sections from donors diagnosed with mild to moderate AKI in order to increase the translatability of murine research to clinical settings. We used spatial transcriptomics and single cell RNA sequencing to identify five distinct human KRM subpopulations. Using the AddModuleScore function in Seurat, we were able to compare the murine KRM transcriptional profiles from pre and post-AKI to the human KRM subpopulations. As a result, we identified four orthologous to known murine KRM subpopulations. The remaining population was identified in the kidney cortex and expresses a profile similar to activate microglia, the resident macrophage population in the brain. Again, we used AddModuleScore to determine a set of marker genes that will allow for the identification of KRM subsets across species and injury.
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Project description:Kidney macrophages are comprised of both monocyte-derived and tissue resident populations; however, the heterogeneity of kidney macrophages and factors that regulate their heterogeneity are poorly understood. Herein, we performed single cell RNA sequencing (scRNAseq), fate mapping, and parabiosis to define the cellular heterogeneity of kidney macrophages in healthy mice. Our data indicate that healthy mouse kidneys contain four major subsets of monocytes and two major subsets of kidney resident macrophages (KRM) including a population with enriched Ccr2 expression, suggesting monocyte origin. Surprisingly, fate mapping data using the newly developed Ms4a3Cre Rosa Stopf/f TdT model indicate that less than 50% of Ccr2+ KRM are derived from Ly6chi monocytes. Instead, we find that Ccr2 expression in KRM reflects their spatial distribution as this cell population is almost exclusively found in the kidney cortex. We also identified Cx3cr1 as a gene that governs cortex specific accumulation of Ccr2+ KRM and show that loss of Ccr2+ KRM reduces the severity of cystic kidney disease in a mouse model where cysts are mainly localized to the kidney cortex. Collectively, our data indicate that Cx3cr1 regulates KRM heterogeneity and niche-specific disease progression.
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