Abstract
Mesenchymal stromal cells (MSCs) are used to treat infectious and immune diseases and disorders; however, its mechanism(s) remain incompletely defined. Here we find that bone marrow stromal cells (BMSCs) lacking Pinch1/2 proteins display dramatically reduced ability to suppress lipopolysaccharide (LPS)-induced acute lung injury and dextran sulfate sodium (DSS)-induced inflammatory bowel disease in mice. Prx1-Cre; Pinch1f/f; Pinch2−/− transgenic mice have severe defects in both immune and hematopoietic functions, resulting in premature death, which can be restored by intravenous injection of wild-type BMSCs. Single cell sequencing analyses reveal dramatic alterations in subpopulations of the BMSCs in Pinch mutant mice. Pinch loss in Prx1+ cells blocks differentiation and maturation of hematopoietic cells in the bone marrow and increases production of pro-inflammatory cytokines TNF-α and IL-1β in monocytes. We find that Pinch is critical for 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. Administration of recombinant Mbl2 protein restores the lethality induced by Pinch loss in mice. Collectively, we demonstrate that the novel Pinch-Cxcl12-Mbl2 signaling pathway promotes the interactions between bone and liver to modulate immunity and hematopoiesis and may provide a useful therapeutic target for immune and infectious diseases.
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Data availability
All data supporting the findings of this study are available within the article and its Extended Data files or from the corresponding authors upon reasonable request. Source data are provided with this paper. ScRNA-seq data have been deposited in Gene Expression Omnibus under accession No. GSE152217 and LC–MS/MS data have been deposited in PRIDE Archive under accession No. PXD043019.
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Acknowledgements
The authors acknowledge the assistance of Core Research Facilities of Southern University of Science and Technology. This work was supported, in part, by the National Natural Science Foundation of China Grants (81991513, 82230081, 82250710175, 82261160395, 82004395), the National Key Research and Development Program of China Grants (2019YFA0906004), the Guangdong Provincial Science and Technology Innovation Council Grant (2017B030301018), and the Science and Technology Innovation Commission of Shenzhen Municipal Government Grants (CYJ20220818100617036, ZDSYS20140509142721429). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Study design: GX, TH, BZ, GS, XB and HC. Study conduct and data collection: TH, ZB, GS, YL, QY, SL, GM, WJ, XW, YZ, DG, QY, TC and GX. Data analysis: TH, BZ, HC and GX. Data interpretation: GX, CL, TH, SH, TC, XB and DC. Drafting the manuscript: GX and TH. TH, HC and GX take the responsibility for the integrity of the data analysis.
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The animal experiments conformed to the guidelines and regulatory standards of the Institutional Animal Care and Use Committee (IACUC) at the Southern University of Science and Technology, No. SUSTC-JY2019153.
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He, T., Zhou, B., Sun, G. et al. The bone–liver interaction modulates immune and hematopoietic function through Pinch-Cxcl12-Mbl2 pathway. Cell Death Differ 31, 90–105 (2024). https://doi.org/10.1038/s41418-023-01243-9
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DOI: https://doi.org/10.1038/s41418-023-01243-9