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Abstract
Background Mesenchymal stromal/stem cells (MSCs) are multipotent cells that can differentiate into multiple cell types. MSCs display various beneficial properties against infectious and immune diseases and disorders, driven by their paracrine effects through trophic factors; however, their mechanism(s) remain incompletely defined. Focal adhesions (FAs) are a vital mechanical linkage that connects the extracellular matrix and cytoskeleton, allowing for crucial cell-environment communication. Recent studies have highlighted the essential roles of FA proteins in inflammatory-related illnesses. Hence, this study aims to elucidate the potential roles of Pinch, one of FA proteins, in the bone marrow stromal cells (BMSCs).
Methods We generated Pinch1/2 double knockout transgenic mice and collected their bone marrow cells for single-cell RNA-sequencing combined with 4D proteomics analysis. The results were validated through various in vitro and in vivo experiments. Additionally, we conducted two mouse disease models to enhance the translational significance.
Results BMSCs lacking Pinch1/2 display a dramatically reduced ability to suppress lipopolysaccharide (LPS)-induced acute lung injury and dextran sulfate sodium (DSS)-induced inflammatory bowel disease in mice (IDDF2024-ABS-0142 Figure 1). Prx1-Cre; Pinch1f/f; Pinch2−/− transgenic mice severely reduced chondrocyte proliferation, leading to dwarfism and severe osteopenia (IDDF2024-ABS-0142 Figure 2). Moreover, they have severe defects in both immune and hematopoietic functions, resulting in premature death (IDDF2024-ABS-0142 Figure 3), which can be restored by intravenous injection of wild-type BMSCs (IDDF2024-ABS-0142 Figure 4). Single-cell sequencing analyses reveal dramatic alterations in subpopulations of the BMSCs in Pinch mutant mice (IDDF2024-ABS-0142 Figure 2). We find that Pinch is critical for the expression of Cxcl12 in BMSCs; reduced production of Cxcl12 protein from Pinch-deficient BMSCs reduces expression of the Mbl2 complement in hepatocytes, thus impairing the innate immunity and thereby contributing to infection and death (IDDF2024-ABS-0142 Figure 5). Administration of recombinant Mbl2 protein restores the lethality induced by Pinch loss in mice (IDDF2024-ABS-0142 Figure 5).
Conclusions We demonstrate that the novel Pinch-Cxcl12-Mbl2 signaling pathway promotes the interactions between bone and liver to modulate immunity and hematopoiesis. It provides valuable insights for the improved utilization of BMSCs to mitigate the occurrence of infectious and immune-mediated disorders.