Lipid Nanoparticle Delivery of Mesenchymal Stromal Cell-Derived microRNA 187-3p as a First-in-Class Therapy for Myocardial Dysfunction in Sepsis
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".