Msx1 and Msx2 are required for endothelial-mesenchymal transformation of the atrioventricular cushions and patterning of the atrioventricular myocardium

<p>Abstract</p> <p>Background</p> <p><it>Msx1 </it>and <it>Msx2</it>, which belong to the highly conserved <it>Nk </it>family of homeobox genes, display overlapping expression patterns and redundant functions in multiple tissues and organs during vertebrate development. <it>Msx1 </it>and <it>Msx2 </it>have well-documented roles in mediating epithelial-mesenchymal interactions during organogenesis. Given that both <it>Msx1 </it>and <it>Msx2 </it>are crucial downstream effectors of Bmp signaling, we investigated whether <it>Msx1 </it>and <it>Msx2 </it>are required for the Bmp-induced endothelial-mesenchymal transformation (EMT) during atrioventricular (AV) valve formation.</p> <p>Results</p> <p>While both <it>Msx1-/- </it>and <it>Msx2-/- </it>single homozygous mutant mice exhibited normal valve formation, we observed hypoplastic AV cushions and malformed AV valves in <it>Msx1-/-; Msx2-/- </it>mutants, indicating redundant functions of <it>Msx1 </it>and <it>Msx2 </it>during AV valve morphogenesis. In <it>Msx1/2 </it>null mutant AV cushions, we found decreased Bmp2/4 and <it>Notch1 </it>signaling as well as reduced expression of <it>Has2</it>, <it>NFATc1 </it>and <it>Notch1</it>, demonstrating impaired endocardial activation and EMT. Moreover, perturbed expression of chamber-specific genes <it>Anf</it>, <it>Tbx2</it>, <it>Hand1 </it>and <it>Hand2 </it>reveals mispatterning of the <it>Msx1/2 </it>double mutant myocardium and suggests functions of <it>Msx1 </it>and <it>Msx2 </it>in regulating myocardial signals required for remodelling AV valves and maintaining an undifferentiated state of the AV myocardium.</p> <p>Conclusion</p> <p>Our findings demonstrate redundant roles of <it>Msx1 </it>and <it>Msx2 </it>in regulating signals required for development of the AV myocardium and formation of the AV valves.</p

Circulating apoptotic microparticles in systemic lupus erythematosus patients drive the activation of dendritic cell subsets and prime neutrophils for NETosis

\u3cp\u3eOBJECTIVE: Circulating chromatin-containing apoptotic material and/or neutrophil extracellular traps (NETs) have been proposed to be an important driving force for the antichromatin autoimmune response in patients with systemic lupus erythematosus (SLE). The aim of this study was to determine the exact nature of microparticles in the circulation of SLE patients and to assess the effects of the microparticles on the immune system.\u3c/p\u3e\u3cp\u3eMETHODS: We analyzed microparticles isolated from the plasma of patients with SLE, rheumatoid arthritis (RA), and systemic sclerosis (SSc), as well as from healthy subjects. The effects of the microparticles on blood-derived dendritic cells (DCs) and neutrophils were assessed by flow cytometry, enzyme-linked immunosorbent assay, and immunofluorescence microscopy.\u3c/p\u3e\u3cp\u3eRESULTS: In SLE patients, we identified microparticles that were highly positive for annexin V and apoptosis-modified chromatin that were not present in healthy subjects or in RA or SSc patients. These microparticles were mostly CD31+/CD45- (endothelial), partly CD45+/CD66b+ (granulocyte), and negative for B and T cell markers. Microparticles isolated from the plasma of SLE patients increased the expression of the costimulatory surface molecules CD40, CD80, CD83, and CD86 and the production of proinflammatory cytokines interleukin-6, tumor necrosis factor, and interferon-α by blood-derived plasmacytoid DCs (PDCs) and myeloid DCs (MDCs). SLE microparticles also primed blood-derived neutrophils for NETosis. Microparticles from healthy subjects and from RA or SSc patients exhibited no significant effects on MDCs, PDCs, and NETosis.\u3c/p\u3e\u3cp\u3eCONCLUSION: Circulating microparticles in SLE patients include a population of apoptotic cell-derived microparticles that has proinflammatory effects on PDCs and MDCs and enhances NETosis. These results underline the important role of apoptotic microparticles in driving the autoimmune response in SLE patients.\u3c/p\u3