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Transcriptomic Analysis of Circulating Extracellular Vesicles and Serum during the Perioperative period of Fontan and Glenn Surgery

ABSTRACT: Single-ventricle defects are palliatively corrected using the Glenn and Fontan procedures that provide lifesaving relief but lead to early mortality rates and poor prognosis post-operatively. The pathophysiology of these complications is diverse, and there are no clear predictors for these outcomes. As such, we aimed to identify novel biomarkers for single-ventricle associated outcomes through the characterization of the serum transcriptome and small extracellular vesicles (sEVs). We report on molecular responses in serum and sEVs pre-operatively and post-operatively in patients undergoing either Glenn or Fontan operations. We found that transcriptomes of serum RNA and sEV RNA are distinctly different, whereas differences between the Fontan and Glenn transcriptomes did not show any significant changes. An in vitro wound healing assay further confirmed that post-operative sEVs have higher angiogenic potential. Moreover, we used a partial-least square regression model to identify 100 RNAs and 50 microRNAs that are involved in angiogenesis-related pathways and accurately predict our wound healing results and compared them with our previously published models of ovine Fontan surgery. Lastly, an EV-origin analysis showed decreased secretion of sEV from cardiac tissue in post-operative samples and increased secretion of sEVs from stomach and nervous tissue. Overall, this study provided evidence that the circulating sEVs transcriptome are potent biomarkers and demonstrated the role of sEVs as a possible mediator for formation of veno-venous collaterals.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269879 | GEO | 2024/12/20

REPOSITORIES: GEO

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Project description:Bacterial infections of wounds are associated with poor healing and worse scarring. We sought to identify transcriptomic patterns associated with impaired healing of wounds infected with Klebsiella pneumoniae (K.p.) or Pseudomonas aeruginosa (P.a.) using a rabbit ear wound model. Wounds created on post-operative day (POD) 0 were infected on POD3, within the inflammatory phase of healing. On POD4 the infected wounds were harvested for microarray/transcriptome analysis. Other wounds with 24-hour infections were treated with topical antibiotic to promote biofilm formation and harvested on POD6 or POD12. On POD4 before antibiotic treatment, both wounds contained elevated transcripts that enriched predominantly into inflammation/infection-response pathways and functions characteristic of infiltrating leukocytes. But there were 5-fold more elevated transcripts in P.a.- than K.p.-infected wounds. Additionally, unique to P.a.-infected wounds, was a minor network of inflammation/infection-response molecules with predicted upstream regulation predominated by type I interferons. Also on POD4, Dnr-transcripts of both wounds were enriched into stress-response pathways such as EIF2 signaling. But there were 8-fold more Dnr-transcripts in P.a.- than K.p.-infected wounds, and many more of them enriched in the function, cell death, suggesting that resident dermal cells of P.a.-infected wounds failed to survive a more destructive P.a. infection. On POD6, following two days of antibiotic treatment, the biofilm-colonized wounds expressed magnitudes fewer inflammation and stress-response transcripts. However, a single regulatory network of P.a.-infected wounds was found to consist of Upr-transcripts enriching immune/infection-response functions predicted to be regulated by type I interferons, which was similar to the network unique to P.a.-infected wounds on POD4. On POD12, genes expressed by K.p.-infected wounds suggesting healing, while for P.a.-infected wounds they suggested stalled healing. The similarities and differences between the wound responses to these infections further define the molecular foundations of healing impaired by infections. Rabbit ear Wounds created on post-operative day (POD) 0 were infected with Klebsiella pneumoniae (K.p.) or Pseudomonas aeruginosa (P.a.) on POD3 and harvested on POD4 for RNA extraction. Other wounds with 24-hour infections were treated with topical antibiotic to promote biofilm formation and harvested on POD6 or POD12.

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Transcriptomic Analysis of Circulating Extracellular Vesicles and Serum during the Perioperative period of Fontan and Glenn Surgery

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