Myocardial ischemia-reperfusion (MIR) injury drives adverse remodeling and heart failure after ST-elevation myocardial infarction (STEMI), yet no therapy directly targets the fibrotic response. Here, we developed a good manufacturing practice-compatible extracellular vesicle (EV)-enriched secretome from bone marrow mesenchymal stromal cells and identified a laminin-521-based production strategy suitable for clinical translation. The EV-enriched secretome exhibited in vitro immunomodulatory activity, and in murine MIR-injury models, treatment preserved left ventricular ejection fraction, reduced platelet-derived growth factor receptor beta (PDGFRβ)-associated myofibroblast activation quantified by positron emission tomography (PET) imaging, attenuated fibrosis, and promoted reparative macrophage polarization. In a clinically relevant porcine ischemia-reperfusion model, intracoronary administration was cardioprotective. We further developed a clinically approved PDGFRβ-targeted PET-imaging platform for longitudinal assessment of fibrotic activity in STEMI patients, where preliminary observations suggest that myofibroblast activation persists for up to 2 months after STEMI in selected patients. Together, these findings establish a translational therapeutic-diagnostic framework for individualized management of MIR injury.
Karl-Henrik Grinnemo, Ken Braesch-Andersen, Johan O. Wedin et al.· Cell Stem Cell· 1 citation
Oncolytic herpes simplex virus type-1 (HSV1)–based therapies engage innate immune responses, including natural killer (NK) cells, which are regarded as antiviral effector cells that eliminate virus-infected tumor targets. In this study, we examined interactions between the HSV1–derived oncolytic virus HSV1716 and primary human NK cells. Co-culture experiments revealed increased activation and degranulation of NK cells in response to HSV1716-infected tumor cells, despite the downregulation of ligands for NK-cell activating receptors on infected targets. Following co-culture with infected tumor cells, but not after incubation with viral inoculum alone, viral gene expression and increased viral copy numbers were detected in NK cells, indicating enhanced viral acquisition and persistence associated with target-cell contact. HSV1716-infected NK cells displayed impaired tumor cell killing ability. Single-cell sequencing analysis revealed downregulation of key NK effector genes alongside alterations in stress-response pathways in HSV1716 infected NK cells. Together, these findings demonstrate that primary human NK cells are infected by HSV1716 and undergo functional and phenotypic changes, leading to a diminished cytotoxic capacity. Given the emerging role of NK cell–based therapies in cancer, these findings may be relevant for the design and timing of oncolytic virus–based strategies in the future.
K. Susek, D. Holla, C. Marsal et al.· Frontiers in Immunology· 0 citations
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