Publications

Background: We have reported that intramyocardial transfer of plasmid encoding human placental growth factor (phPlGF) augments myocardial angiogenesis, inhibits myocardial apoptosis and left ventri...

Endothelial cells (ECs) line blood vessels, regulate homeostatic processes (blood flow, immune cell trafficking), but are also involved in many prevalent diseases. The increasing use of high-throughput technologies such as gene expression microarrays and (single cell) RNA sequencing generated a wealth of data on the molecular basis of EC (dys-)function. Extracting biological insight from these datasets is challenging for scientists who are not proficient in bioinformatics. To facilitate the re-use of publicly available EC transcriptomics data, we developed the endothelial database EndoDB, a web-accessible collection of expert curated, quality assured and pre-analyzed data collected from 360 datasets comprising a total of 4741 bulk and 5847 single cell endothelial transcriptomes from six different organisms. Unlike other added-value databases, EndoDB allows to easily retrieve and explore data of specific studies, determine under which conditions genes and pathways of interest are deregulated and assess reprogramming of metabolism via principal component analysis, differential gene expression analysis, gene set enrichment analysis, heatmaps and metabolic and transcription factor analysis, while single cell data are visualized as gene expression color-coded t-SNE plots. Plots and tables in EndoDB are customizable, downloadable and interactive. EndoDB is freely available at https://vibcancer.be/software-tools/endodb, and will be updated to include new studies.

In brief: In large fracture calluses, skeletal progenitors activate the chondrogenesis program, whereas in smaller calluses, direct osteogenesis is the preferred path. Here, the authors show that lipid availability determines whether skeletal stem cells repair a fracture through endochondral bone formation or direct ossification.

Non‐structural matri‐cellular proteins (MCPs) modulate the process of heart failure (HF) by acting on different cardiac cellular compartments. Here, we investigated whether MCPs, including TSP2, SPARC or osteoglycin (OGN), may affect cardiac inflammation. Therefore, TSP‐2, SPARC and OGN‐null animals and their WT littermates were submitted to human Coxsackievirus B3 (CVB3)‐induced myocarditis. Whereas the absence of TSP‐2 or SPARC increased cardiac inflammation, necrosis and overall mortality as compared to WT at 14 days, resulting in systolic dysfunction at 35 days, lack of OGN was protective. Increased cardiac inflammation and injury was caused by decreased activation of the anti‐inflammatory T‐regulatory cells (TSP‐2‐null) and increased trans‐endothelial leukocyte migration (SPARC‐null). Decreased cytokine activation caused less cardiac inflammation in OGN‐null. Finally, over expression of TSP‐2 or SPARC in WT hearts with AAV9‐TSP2 or AdVSPARC significantly reduced cardiac inflammation and injury. In conclusion, whereas increased SPARC or TSP‐2 protect against cardiac necrosis and failure during viral myocarditis, OGN is detrimental.

Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1α (HIF1α) in the induction of miR122 and identified the oxygen-sensing prolyl hydroxylase domain 1 (PHD1) as a miR122 target. Further studies indicated that HIF1α-dependent induction of miR122 participated in a feed-forward pathway for liver protection via the enhancement of hepatic HIF responses through PHD1 repression. Moreover, pharmacologic studies utilizing nanoparticle-mediated miR122 overexpression demonstrated attenuated liver injury. Finally, proof-of-principle studies in patients undergoing orthotopic liver transplantation showed elevated miR122 levels in conjunction with the repression of PHD1 in post-ischemic liver biopsies. Taken together, the present findings provide molecular insight into the functional role of miR122 in enhancing hepatic ischemia tolerance and suggest the potential utility of pharmacologic interventions targeting miR122 to dampen hepatic injury during liver transplantation.