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Abstract: SA-PO111

Platelet-Instructed SPP1 Macrophages Drive Myofibroblast Activation in Fibrosis in a CXCL4-Dependent Manner

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Hoeft, Konrad, University Hospital Aachen Institute of Experimental Medicine and Systems Biology, Aachen, Germany
  • Schaefer, Gideon, University Hospital Aachen Institute of Experimental Medicine and Systems Biology, Aachen, Germany
  • Schumacher, David, University Hospital Aachen Institute of Experimental Medicine and Systems Biology, Aachen, Germany
  • Kim, Hyoijn, University Hospital Aachen Institute of Experimental Medicine and Systems Biology, Aachen, Germany
  • Klinkhammer, Barbara Mara, Universitatsklinikum Aachen Institut fur Pathologie, Aachen, Germany
  • Kuppe, Christoph, University Hospital Aachen Institute of Experimental Medicine and Systems Biology, Aachen, Germany
  • Boor, Peter, Universitatsklinikum Aachen Institut fur Pathologie, Aachen, Germany
  • Hayat, Sikander, University Hospital Aachen Institute of Experimental Medicine and Systems Biology, Aachen, Germany
  • Kramann, Rafael, University Hospital Aachen Institute of Experimental Medicine and Systems Biology, Aachen, Germany

Group or Team Name

  • Kramann Laboratory for Translational Cardiovascular and Kidney Research
Background

Fibrosis represents the common end-stage of chronic organ injury independent of the initial insult, destroying tissue architecture and driving organ failure. Immune cells are key players in fibrosis, which regulate mesenchymal cell activation. However, the signals driving profibrotic immune cell differentiation and subsequent fibroblast crosstalk remain ill-defined.

Methods

We analyzed single cell RNA sequencing (scRNA-seq) data of mice after myocardial infarction (MI) to identify profibrotic immune cells. To validate CXCL4 as a mediator of fibrosis we investigated the effect of a CXCL4-KO in monocytes in vitro, as well as in mouse models of MI and kidney ischemia reperfusion injury (IRI). To elucidate profibrotic macrophage-fibroblast crosstalk we performed single nuclear RNA sequencing (snRNA-seq) of WT and Cxcl4-/- mice after IRI. The role of platelet-derived CXCL4 was assessed by co-culturing WT and CXCL4-/- platelets with PBMC. Lastly, we analyzed SPP1 macrophages in open-source scRNA-seq data of human heart failure (HF) and chronic kidney disease (CKD) as well as via immunostaining/in situ-hybridisation in a cohort of 43 human kidneys.

Results

We discovered a profibrotic macrophage population marked by Spp1 (Spp1 Mac), which expands after MI. Trajectory inference analysis of Spp1 Mac identified CXCL4 as one of the top upregulated genes during Spp1 Mac differentiation. In vitro and in vivo studies demonstrated that loss of Cxcl4 abrogates Spp1 Mac differentiation and fibrosis after MI and IRI. SnRNA-seq of WT and Cxcl4-/- mice after IRI revealed that macrophages orchestrate fibroblast activation via Spp1, Fn1 and Sema3 crosstalk. Importantly, we uncovered that platelets drive profibrotic Spp1 Mac differentiation via CXCL4. Lastly, we show that SPP1 Mac expand in human HF and CKD and that SPP1+ Mac correlate closely with COL1A1 expression in 43 human kidneys.

Conclusion

We identified a novel profibrotic macrophage population defined by Spp1 expression and demonstrate that Spp1 macrophage differentiation is driven by CXCL4. Strikingly, we uncovered an unexpected link between platelets, the main source of CXCL4, macrophages and fibrosis. Targeting platelet-macrophage interaction could serve as a springboard for novel strategies aimed at mitigating fibrosis.