The bone-liver interaction modulates immune and hematopoietic function through Pinch-Cxcl12-Mbl2 pathway

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Mesenchymal stromal cells (MSCs) are utilized for treating immune and infectious diseases, but their precise mechanisms are not fully understood.
• The role of Pinch proteins in MSC function and their impact on immune regulation requires further elucidation.

Purpose of the Study:

• To investigate the function of Pinch1/2 proteins in bone marrow stromal cells (BMSCs) and their role in immune and hematopoietic regulation.
• To identify the molecular pathways by which Pinch proteins modulate immunity and hematopoiesis.

Main Methods:

• Utilized Prx1-Cre; Pinch1^f/f; Pinch2^-/- transgenic mice to study the effects of Pinch deficiency in BMSCs.
• Employed single-cell sequencing to analyze BMSC subpopulations and hematopoietic cell differentiation.
• Assessed inflammatory responses using lipopolysaccharide (LPS)-induced acute lung injury and dextran sulfate sodium (DSS)-induced inflammatory bowel disease models.
• Investigated the expression of Cxcl12 in BMSCs and Mbl2 complement in hepatocytes.

Main Results:

• Mice lacking Pinch1/2 proteins in BMSCs exhibited severe immune and hematopoietic defects, leading to premature death.
• Pinch deficiency in BMSCs impaired hematopoietic cell maturation and increased pro-inflammatory cytokine production (TNF-α, IL-1β) in monocytes.
• Loss of Pinch reduced Cxcl12 expression in BMSCs, subsequently decreasing Mbl2 complement in hepatocytes and impairing innate immunity.
• Administration of recombinant Mbl2 protein rescued lethality in mice with Pinch-deficient BMSCs.

Conclusions:

• The Pinch-Cxcl12-Mbl2 signaling pathway is crucial for modulating immunity and hematopoiesis by mediating bone-liver interactions.
• Targeting this pathway offers a potential therapeutic strategy for immune and infectious diseases.