Role of Interleukin 17A in Aortic Valve Inflammation in Apolipoprotein E-deficient Mice

Summary:Interleukin 17A(IL 17A)is reported to be involved in many inflammatory processes,but its role in aortic valve diseases remains unknown.We examined the role of IL17A based on an ApoE^-/-mouse model with strategies as fed with high-fat diet or treated with ILI7A monoclonal antibody(mAb).12 weeks of high-fat diet feeding can elevate cytokines secretion,inflammatory cells infiltration and myofibroblastic transition of valvular interstitial cells(VICs)in aortic valve.Moreover,diet-induction accelerated interleukin 17 receptor A(IL17RA)activation in VICs.In an IL17A inhibition model,the treatment group was intra-peritoneally injected with anti-IL17A mAb while controls received irrelevant antibody.Functional blockade of IL17A markedly reduced cellular infiltration and transition in aortic valve.To investigate potential mechanisms,NF-kB was co-stained in IL17RA^+VICs and IL17RA macrophages,and further confirmed by Western blotting in VICs.High-fat diet could activate NF-kB nuclear translocation in IL17RA^+VICs and IL17RA^+macrophages and this process was depressed after IL17A mAb-treatment.In conclusion,high-fat diet can lead to IL17A upregulation,VICs myofibroblastic transition and inflammatory cells infiltration in the aortic value of ApoE^-/-mice.Blocking IL17A with IL17A mAb can alleviate aortic valve inflammatory states.

Deciphering transcriptome alterations in bone marrow hematopoiesis at single-cell resolution in immune thrombocytopenia

Immune thrombocytopenia(ITP)is an autoimmune disorder,in which megakaryocyte dysfunction caused by an autoimmune reaction can lead to thrombocytopenia,although the underlying mechanisms remain unclear.Here,we performed single-cell transcriptome profiling of bone marrow CD34+hematopoietic stem and progenitor cells(HSPCs)to determine defects in megakaryopoiesis in ITP.Gene expression,cell-cell interactions,and transcriptional regulatory networks varied in HSPCs of ITP,particularly in immune cell progenitors.Differentially expressed gene(DEG)analysis indicated that there was an impaired megakaryopoiesis of ITP.Flow cytometry confirmed that the number of CD9+and HES1+cells from Lin−CD34+CD45RA−HSPCs decreased in ITP.Liquid culture assays demonstrated that CD9+Lin−CD34+CD45RA−HSPCs tended to differentiate into megakaryocytes;however,this tendency was not observed in ITP patients and more erythrocytes were produced.The percentage of megakaryocytes differentiated from CD9+Lin−CD34+CD45RA−HSPCs was 3-fold higher than that of the CD9−counterparts from healthy controls(HCs),whereas,in ITP patients,the percentage decreased to only 1/4th of that in the HCs and was comparable to that from the CD9−HSPCs.Additionally,when co-cultured with pre-B cells from ITP patients,the differentiation of CD9+Lin−CD34+CD45RA−HSPCs toward the megakaryopoietic lineage was impaired.Further analysis revealed that megakaryocytic progenitors(MkP)can be divided into seven subclusters with different gene expression patterns and functions.The ITP-associated DEGs were MkP subtype-specific,with most DEGs concentrated in the subcluster possessing dual functions of immunomodulation and platelet generation.This study comprehensively dissects defective hematopoiesis and provides novel insights regarding the pathogenesis of ITP.

A Novel Method to Improve the Physical Property and Biocompatibility of Decellularized Heart Valve Scaffold with Sericin and Polydopamine

Cardiac valve replacement is an effective method to treat valvular heart disease.Artificial valves used routinely in clinic still have defects.In our study,we explored a novel method to modify the performance of Decellularized Heart Valve(DHV)scaffold.The decellularized porcine aortic valve was prepared using sequential hydrophile and lipophile solubilization method.The sericin was extracted from silk fibroin-deficient silkworm cocoon by lithium bromide method.First,DHV was immersed in sericin solution to produce the sericin–DHV composite scaffold.Then,we modified the DHV by making a Polydopamine(PDA)coating on the DHV first and then binding the sericin.The physical properties and biological compatibility of our composite scaffold were assessed in vitro and in vivo.Sericin were successfully prepared,combined to DHV and improved its biocompatibility.PDA coating further promoted the combination of sericin on DHV and improved the physical properties of scaffolds.The decay rate of our modified valve scaffold was decreased in vivo and it showed good compatibility with blood.In conclusion,our modification improved the physical properties and biocompatibility of the valve scaffold.The combination of PDA and sericin promoted the recellularization of decellularized valves,showing great potential to be a novel artificial valve.