bims-evecad 2026-08-09 papers

Issue of 2026–08–09
five papers selected by
Cliff Dominy

Front Cell Dev Biol. 2026 ;14 1882071

Non-coding RNA-driven cardiovascular immunometabolic reprogramming: from inflammatory endotypes to therapeutic opportunities.

Yang Sheng, Yao Yao, Hengcang Wang.

Cardiovascular disease is increasingly recognized as a heterogeneous immunometabolic disorder shaped by inflammation, metabolic rewiring, endothelial dysfunction, mitochondrial stress, and tissue remodeling across diverse cell types. This review provides a hypothesis-generating conceptual synthesis of non-coding RNA-driven cardiovascular immunometabolic reprogramming from an inflammatory endotype-oriented perspective. Because ncRNA profiling has not yet prospectively assigned cardiovascular patient cohorts to validated inflammatory endotypes, we frame mechanism-based endotypes as complementary research constructs rather than clinically deployable diagnostic categories. We discuss how conventional disease labels, including atherosclerosis, myocardial infarction, heart failure, hypertension, and cardiomyopathy, may be cross-mapped to dominant mechanisms such as athero-inflammation, sterile ischemic injury, fibro-inflammatory remodeling, metabolic inflammation, and vascular immune-endothelial dysfunction. We summarize how microRNAs, long non-coding RNAs, circular RNAs, and extracellular vesicle-associated RNA species regulate macrophage cholesterol handling, inflammasome activation, endothelial activation, vascular smooth muscle cell plasticity, cardiomyocyte mitochondrial dysfunction, fibroblast activation, extracellular matrix remodeling, and intercellular communication, with added attention to circRNA tissue-source patterns in cardiac, immune-cell, endothelial, and vascular compartments. We also highlight their context-dependent and cell type-specific actions, which challenge simple protective-versus-pathogenic classifications. Finally, we discuss translational opportunities, including circulating and extracellular vesicle-associated non-coding RNAs as liquid biopsy candidates, RNA-based therapeutics, endotype-enriched study designs, and traditional medicine-inspired multicomponent strategies. Despite barriers related to delivery, specificity, disease stage, species conservation, analytical standardization, and validation, integrated phenotyping, multi-omics profiling, functional perturbation, and biomarker-enriched trials may advance non-coding RNAs as candidate classifiers, regulators, markers, and therapeutic targets in precision cardiovascular medicine.

Keywords: cardiovascular disease; extracellular vesicles; immunometabolic reprogramming; inflammatory endotypes; non-coding RNA; precision therapy

DOI: https://doi.org/10.3389/fcell.2026.1882071

Biosci Rep. 2026 Aug 07. pii: BSR20260067. [Epub ahead of print]

Proteomic analysis of plasma and extracellular vesicles from subjects with impaired vascular health.

Yibo Gao, Lasse G Lorentzen, Emily M Martin, Federica Genovese, Gernot Faustmann, Johanna Grabher-Moser, Beate Tiran, Brigitte M Winklhofer-Roob, Michael J Davies.

Cardiovascular diseases are the leading cause of mortality worldwide, with atherosclerosis and formation of arterial plaques being a major underlying cause. Rupture or erosion of the plaque fibrous cap can result in thrombus formation, arterial occlusion, and a stroke or myocardial infarction. Plaque changes, and endothelial cell barrier leakiness, may result in material leakage, including proteins and fragments into plasma either directly or in extracellular vesicles (EVs). Here we report comparative LC-MS/MS analyses of plasma-derived EVs and plasma from subjects with impaired vascular status and healthy controls. Analysis of plasma-derived EVs detected 7228 peptides and 763 proteins, with 87 proteins being differentially-abundant with these including arterial-cell species. Sub-group analysis based on biological sex showed no statistically-significant differences for males, whereas females exhibited 8 differentially-expressed proteins. Subject age effects were minimal. Plasma analysis detected 4366 peptides and 497 proteins, with 188 proteins being significantly altered in abundance between the groups. Subgroup analysis by biological sex revealed 103 differentially-expressed proteins in females and 84 in males. No differences were detected in specific collagen fragments. Gene Set Enrichment Analysis revealed altered biological processes related to immune regulation, humoral immune response, proteolysis, and cellular components including plasma lipoprotein particle, extracellular space, and membrane-associated structures. KEGG pathway analysis emphasized enrichment of pathways linked to complement and coagulation cascades, platelet activation, focal adhesion, endocytosis, and inflammation. Together, these data illustrate the potential of LC-MS/MS to examine the role of inflammation and arterial wall cells in shaping the proteome of EVs and plasma in health and disease.

Keywords: Extracellular vesicles; biomarkers; cardiovascular disease; extracellular matrix; protein degradation; proteomics

DOI: https://doi.org/10.1042/BSR20260067

Regen Ther. 2026 Dec;33 101161

Impact of secretome containing extracellular vesicles from human induced pluripotent stem cell-derived cardiomyocytes.

Yuki Saito, Kazuaki Takemura, Junya Aoyama, Sawako Hibino, Kouichi Hasegawa, Yoshiki Sawa.

Introduction: Cell transplantation therapy using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has shown promise for ischemic heart disease. Although paracrine effects mediated by the secretome are recognized as key mechanisms underlying the therapeutic effects of hiPSC-CMs, dynamic changes in the secretome profile during the manufacturing of hiPSC-CMs remain poorly understood. This study was aimed at elucidating the secretome dynamics of clinical-grade hiPSC-CMs to identify their "mode of action" (MoA) and "candidate quality attributes."
Methods: We integrated multiomics profiling, including total RNA-sequencing, proteome analysis, and extracellular vesicle (EV)-derived microRNA-sequencing, with functional assays (cell proliferation, cell migration, and endothelial tube formation) to analyze samples obtained at different time points in the hiPSC-CM manufacturing process (Day 4-25).
Results: High-purity hiPSC-CMs (>95% cardiac troponin T-positivity) exhibited distinct transcriptomic maturation between Day 16 and Day 25, characterized by the upregulation of cardiac marker genes. Proteomic clustering revealed four distinct stages, with functional transition from proliferation-centric signaling to tissue-repair signaling. Notably, the purified Day 25 secretome showed a qualitative shift toward a platelet-derived growth factor- and stromal cell-derived factor 1-rich profile. Simultaneously, EVs from the Day 25 secretome were enriched in "myomiRs" (miR-133b, -208b, -499b) and multiple anti-proliferative miRNAs (let-7e-5p, miR-145-5p). Functionally, the Day 25 secretome significantly enhanced mesenchymal stem/stromal cell (MSC) migration and promoted the formation of mature, highly branched endothelial tubes compared with the secretome from earlier stages.
Conclusions: The hiPSC-CM secretome containing EVs undergoes programmed evolution during manufacturing, with functional transition from promotion of undifferentiated growth to complex tissue repair through stable angiogenesis and MSC recruitment. These findings establish a molecular foundation for the MoA of hiPSC-CM therapy and provide critical candidate quality attributes to ensure the potency and consistency of clinical-grade cardiac products.

Keywords: Angiogenesis; Cardiomyocytes; Human-induced pluripotent stem cells; Regenerative medicine; Secretome; Stem cell therapy

DOI: https://doi.org/10.1016/j.reth.2026.101161

J Immunol. 2026 Aug 04. pii: vkag226. [Epub ahead of print]215(8):

Delivery of extracellular vesicle-associated microRNA-146a regulates human monocyte phenotype and function.

Kyle I Mentkowski, Touba Tarvirdizadeh, Rohan Pandey, Paul J Schiffmacher, Sara Hough, Lisa A Eagler, Fraser J Sim, Jessica Reynolds, Jennifer K Lang.

CCR2+ monocytes are recruited to sites of acute myocardial injury, where they play a critical role in clearing necrotic debris and replenishing the depleted resident macrophage population. Although this response is necessary for early tissue repair, prolonged activation of inflammatory pathways and persistent recruitment of CCR2+ monocytes have been associated with accelerated ventricular remodeling and adverse outcomes. Inhibition of CCR2 has shown promise in preclinical models of myocardial injury and represents a potential therapeutic target. Cardiosphere-derived cell extracellular vesicles (CDC-EVs) have demonstrated cardioprotective effects partly through modulation of the immune response. We investigated whether CDC-EVs regulate inflammatory monocyte trafficking through effects on CCR2 signaling. We found that CDC-EVs reduce the surface availability of CCR2 on human monocytes through an miR-146a-dependent mechanism, resulting in decreased monocyte migration toward CCL2. These findings identify a previously unrecognized mechanism by which CDC-EVs modulate CCR2-dependent monocyte trafficking and provide new insight into how EVs regulate innate immune responses after myocardial injury.

Keywords: CCR2; cardiosphere-derived cells; extracellular vesicles; microRNA; monocyte

DOI: https://doi.org/10.1093/jimmun/vkag226

Phytochem Anal. 2026 Aug 02.

Advances in Exosome-Based Therapy for Cardiovascular Disease: Traditional Chinese Medicine Offering New Avenues for Exosome Functionalization.

Yi Chen, Xiaoyu Sun, Yingbo Ouyang, Rong Miao, Atinga Vallada, Rui Liu, Jingwen Guo, Chuwen Wang, Shiqi Zhang, Lin Li, Zhe Gao, Qilong Wang, Han Zhang, Ling Leng.

BACKGROUND: Cardiovascular diseases (CVDs) remain a leading cause of global mortality and impose a substantial health and economic burden worldwide. Exosomes, as promising endogenous nanocarriers, have emerged as a powerful tool for the prevention and treatment of CVDs. In particular, advanced functionalization strategies have largely enhanced exosomal therapeutic efficacy in vivo. Notably, Traditional Chinese Medicine (TCM) and its bioactive components exert profound regulatory effects on exosomes.
METHODS: In this review, we systematically summarize exosome-based therapeutic strategies for CVDs, along with state-of-art functionalization approaches to optimize exosomal cargo loading and targeted delivery. We further provide a comprehensive overview of TCM-mediated exosomal regulation.
RESULTS: We found that TCM and TCM-derived chemicals can optimize exosomal cargo loading, especially the loading of microRNAs (miRNAs) and bioactive chemicals. More importantly, TCM and chemicals can promote exosomal secretion, which provides new avenues for exosomal-scale production. Besides, there are synergistic effects between exosomes and TCM when co-administered.
CONCLUSION: Collectively, exosome-based systems hold great promise for CVD therapy, and TCM provides novel strategies for exosomal functionalization, which substantially enhances exosomal-mediated therapeutic efficacy for CVDs.

Keywords: Traditional Chinese Medicine; cardiovascular disease; exosomes; functionalization; herbs; secretion

DOI: https://doi.org/10.1002/pca.70085