Dynamic loading of human engineered heart tissue enhances contractile function and drives a desmosome-linked disease phenotype

The role that mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes. However, most EHT systems cannot model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables us to tune preload and have unconstrained contractile shortening of >10%. To do this, three-dimensional (3D) EHTs were integrated with an elastic polydimethylsiloxane strip providing mechanical preload and afterload in addition to enabling contractile force measurements based on strip bending. Our results demonstrated that dynamic loading improves the function of wild-type EHTs on the basis of the magnitude of the applied force, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we used hiPSC-derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy due to mutations in the desmoplakin gene. We demonstrated that manifestation of this desmosome-linked disease state required dyn-EHT conditioning and that it could not be induced using 2D or standard 3D EHT approaches. Thus, a dynamic loading strategy is necessary to provoke the disease phenotype of diastolic lengthening, reduction of desmosome counts, and reduced contractility, which are related to primary end points of clinical disease, such as chamber thinning and reduced cardiac output.Cardiolog

The inhibition of pro-inflammatory cytokines with pentoxifylline in the cardiopulmunary bypass lung

In addition to preventing tissue energy loss during cardiopulmonary bypass. pentoxifylline (Ptx) prevents the production of pro-inflammatory cytokines as well. The aim of this study was to investigate whether Ptx decreases the inflammatory effects of cardiopulmonary bypass on the lungs during open-heart surgery, The patients in the study group (n=15) who were going through an open-heart surgery had 500 mg l(-1) of Ptx added to their prime solution, whereas the patients in the control group (n=10) only received prime solution. Pre-pump and post-pump blood samples were obtained from both groups and assayed for intereukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor alpha (TNFalpha), Lung tissue samples that were obtained after the pump were examined with light microscopy and stained for tissue TNFalpha Non-parametric Wilcoxon test was utilized for statistical evaluation, In the post-pump period, the difference in the IL-6, IL-8 and TNFalpha levels of the two groups was found to be statistically significant (P < 0.005). The tissue samples from the control group had significant staining with TNFalpha. We think that Ptx has important protective effects on the lungs during cardiopulmonary bypass

Natural Occurrence of Autoantibodies against Basement Membrane Proteins in Epidermolysis Bullosa

10.1016/j.jid.2021.10.030Journal of Investigative Dermatolog

PRDM10 directs FLCN expression in a novel disorder overlapping with Birt-Hogg-Dubé syndrome and familial lipomatosis.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, pulmonary cysts, pneumothoraces and renal cell carcinomas. Here, we reveal a novel hereditary disorder in a family with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with BHD based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD. By whole exome sequencing we identified a heterozygous missense variant (p.(Cys677Tyr)) in a zinc-finger encoding domain of the PRDM10 gene which co-segregated with the phenotype in the family. We show that PRDM10Cys677Tyr loses affinity for a regulatory binding motif in the FLCN promoter, abrogating cellular FLCN mRNA and protein levels. Overexpressing inducible PRDM10Cys677Tyr in renal epithelial cells altered the transcription of multiple genes, showing overlap but also differences with the effects of knocking out FLCN. We propose that PRDM10 controls an extensive gene program and acts as a critical regulator of FLCN gene transcription in human cells. The germline variant PRDM10Cys677Tyr curtails cellular folliculin expression and underlies a distinguishable syndrome characterized by extensive lipomatosis, fibrofolliculomas and renal cell carcinomas