Lipid Nanoparticle Delivery of Mesenchymal Stromal Cell-Derived microRNA 187-3p as a First-in-Class Therapy for Myocardial Dysfunction in Sepsis

Authors:
  • AEAmin M. Ektesabi
    Amin M. Ektesabi
  • MBMaria Carolina Barbosa-Silva
    Maria Carolina Barbosa-Silva
  • JTJames N. Tsoporis
    James N. Tsoporis
  • SMSamantha McWhirter
    Samantha McWhirter
  • CVChirag M. Vaswani
    Chirag M. Vaswani
  • YMYanis Mouloud
    Yanis Mouloud
  • LZLogan W.C. Zettle
    Logan W.C. Zettle
  • AAAbdalla Ahmed
    Abdalla Ahmed
  • SBSabrina Setembre Batah
    Sabrina Setembre Batah
  • JDJean-Francois Desjardins
    Jean-Francois Desjardins
  • SGSahil Gupta
    Sahil Gupta
Preprint
Publisher website
Google Scholar
Abstract
Background: Sepsis-induced myocardial dysfunction is a common and critical complication of sepsis. Extracellular vesicles (EVs) from clonally expanded immortalized mesenchymal stromal cells (ciMSCs) contain microRNAs that may be exploited as therapy. Methods: In mouse models of septic cardiomyopathy induced by caecum ligation and puncture, cardiac function was determined by invasive and echocardiographic assessment. Primary cardiomyocytes derived from foetal murine and human adult ventricular tissue, as well as murine hearts were used for mechanistic studies. Studies using post-mortem human hearts or patient plasma, and clinical and echocardiographic measurements were used to establish translational relevance. Results: In preclinical models of sepsis, intravenous administration of either MSCs or ciMSC-EVs, given after the induction of sepsis, prevented a decrease in myocardial ejection fraction, ventricular inflammation, and mortality compared to placebo or platelet-derived control EVs. EV-microRNA sequencing identified enrichment for microRNA-187a-3p (miR-187) in ciMSC-EVs. miR-187 is anti-inflammatory; with interleukin-6 (IL-6) as its major target. Intravenous delivery of lipid nanoparticle (LNP) encapsulated miR-187 improved cardiac function, reduced inflammation, and enhanced survival of septic mice. In cardiomyocytes and in murine hearts, LNP-miR-187 reduces inflammation and expression of myocardial transcription factors linked to fetal gene reactivation in failing septic hearts. In human septic hearts, low circulating miR-187 levels correlate with reduced cardiac function and high sequential organ failure assessment (SOFA) scores. Conclusion: These findings support the development of first-in-class, cell-free, miRNA-based therapy as a novel approach to treat sepsis-induced cardiomyopathy to address a critical gap in sepsis care. One Sentence Summary: miR-based therapy for sepsis The Clinical Perspective: A. What is NEW? Sepsis accounts for 1 in 5 deaths worldwide. Here, we demonstrate that sepsis-induced myocardial dysfunction represents a discrete, targetable sepsis-trait — a distinct biological abnormality characterized by cardiomyocyte inflammation and fetal gene reactivation. This component contributes to the propagation of organ dysfunction and overall mortality and may respond to focused epigenetic-based interventions. B. What are the Clinical implications? Currently, there are no effective treatments to reduce, limit, or reverse the immune dysfunction component of sepsis that contributes to multiorgan failure, such as sepsis-induced cardiomyopathy. We identify miR-187 as a clinically relevant post-transcriptional regulator of cardiac inflammation and cardiomyocyte gene expression. Intravenous delivery of miR-187 encapsulated in a lipid nanoparticle (LNP) represents a fundamentally distinct, effective and pathogen-agnostic approach to correcting sepsis-induced cardiac dysfunction through modulation of cardiomyocyte inflammatory and metabolic pathways.
Funding Information
  • Nanomedicine Innovation Network
  • Ted Rogers Centre for Heart Research Education Fund
  • Emerging and Pandemic Infections Consortium

This publication has 55 references indexed in Scilit: