bims-evecad 2026-03-08 papers

Issue of 2026–03–08
four papers selected by
Cliff Dominy

NPJ Cardiovasc Health. 2025 Oct 10. pii: 50. [Epub ahead of print]2(1):

Metabolic regulation for the treatment of ischemic heart disease with stem cells and extracellular vesicles.

Shouting Liu, Lei Jin, Jiaxin Zhang, Xinyi Zhang, Yikai Shi, Zheng Tu, Junjun Xu.

Ischemic heart disease (IHD) is a leading cause of mortality worldwide, primarily driven by coronary artery stenosis. Current therapies predominantly slow disease progression, with limited capacity to restore functional myocardium. Worsening metabolic disorders significantly drives heart failure. Emerging evidence suggests that stem cell therapy may improve cardiac metabolism. This review examines metabolic dysregulation in IHD and explores how stem cells and extracellular vesicles could modulate these pathways to support tissue repair.

DOI: https://doi.org/10.1038/s44325-025-00089-z

Gut Microbes. 2026 Dec 31. 18(1): 2635818

Invasion of gut-derived escherichia coli extracellular vesicles exacerbates myocardial ischemia/reperfusion injury.

Junzhuo Wang, Ke Hu, He Lu, Ke Chen, Jian Zhang, Shaojun Wu, Lina Kang, Jun Xie, Biao Xu.

Recent studies have highlighted the close relationship between gut microbiota and the cardiovascular system; however, the precise mechanisms and modes of their interaction remain incompletely understood. Among the various factors involved, bacterial extracellular vesicles (EVs) are often overlooked, despite their potential roles in multiple pathological processes. To investigate the role of bacterial EVs in shaping the inflammatory microenvironment following myocardial ischemia-reperfusion injury, we colonized the intestines of Rosa26.tdTomato reporter mice with Escherichia coli (E. coli) expressing Cre recombinase. Using FACS-beads and immunofluorescence techniques, we found that myocardial ischemia-reperfusion injury in mice significantly enhanced the invasion of gut-derived bacterial EVs. Meanwhile, in patients with ST-segment elevation myocardial infarction, we also confirmed the invasion of bacterial EVs via the FACS-bead method, and there was a significant correlation between extracellular vesicles in peripheral blood and LPS, suggesting that these EVs can be key carriers for LPS translocation. In this pathological process, invading E. coli EVs exacerbate the mobilization and infiltration of systemic and local inflammatory cells, thereby aggravating myocardial damage and impairing cardiac function. Notably, glucagon-like peptide-2 can effectively alleviate inflammatory responses and myocardial injury by inhibiting the translocation of E. coli-derived EVs. In conclusion, our study is the first to confirm the impact of gut-derived EVs on myocardial ischemia-reperfusion injury, revealing that E. coli EVs can amplify inflammatory responses. These findings provide new insights into the gut-heart axis and offer a theoretical basis for the therapeutic potential of glucagon-like peptide-2 in cardiovascular diseases.

Keywords: Cardiac ischemia-reperfusion injury; Escherichia coli; Extracellular Vesicles; Inflammation

DOI: https://doi.org/10.1080/19490976.2026.2635818

Acta Biomater. 2026 Feb 26. pii: S1742-7061(26)00133-9. [Epub ahead of print]

Potential of Intranasal Delivery of Human Mesenchymal Stem Cells and Extracellular Vesicles for Stroke Therapy.

Arshia Arbabian, Tristan Driscoll, Yan Li, Samuel C Grant.

Cerebral ischemic stroke, caused by interrupted cerebral blood flow, remains a leading cause of mortality and long-term disability worldwide. Current FDA-approved therapies-intravenous tissue-type plasminogen activator (tPA) and mechanical thrombectomy-are constrained by narrow time windows (4.5-24 h) and limited accessibility. Mesenchymal stem cells (MSCs) have emerged as promising candidates for neurorestoration, yet their therapeutic efficacy is hindered by poor blood-brain barrier (BBB) penetration and systemic entrapment. Increasing evidence indicates that MSCs exert their therapeutic effects primarily through paracrine mechanisms mediated by extracellular vesicles (EVs), which regulate inflammation, apoptosis, neurogenesis, and angiogenesis. However, translation of EV-based therapies from bench to bedside remains limited, largely due to inefficient delivery and the invasiveness of existing routes. Intranasal (IN) administration offers a minimally invasive approach to bypass the BBB and achieve direct, repeated delivery to the brain. This review synthesizes the mechanistic foundations, preclinical progress, and translational potential of intranasal delivery of MSCs and their EVs for ischemic stroke therapy. We highlight comparative analyses of biodistribution, cellular targets, and functional outcomes across administration routes, emphasizing how route optimization governs therapeutic efficacy. Collectively, these insights establish intranasal delivery as a practical platform for next-generation, cell-free regenerative therapies targeting ischemic brain injury. STATEMENT OF SIGNIFICANCE: Despite extensive investigation of stem-cell-based interventions for ischemic stroke, the influence of administration route on therapeutic outcomes remains poorly defined. This review integrates preclinical and early-phase clinical findings to delineate how delivery pathways shape biodistribution, mechanistic engagement, and neurorepair efficacy of human mesenchymal stem cells (hMSC) and their derived extracellular vesicles (EV). By contrasting conventional intravenous and intra-arterial approaches with the emerging intranasal route, this article emphasizes a non-invasive strategy capable of bypassing the blood-brain barrier, supporting multidose regimens, and sustaining localized repair. Beyond summarizing outcomes, this work clarifies mechanistic drivers-angiogenesis, neurogenesis, and immunomodulation-that can be fine-tuned through delivery design. The synthesis provides a framework for rationally optimizing cell-free hMSC-EV therapeutics and underscores the translational promise of intranasal delivery for clinical stroke management.

Keywords: biodistribution; extracellular vesicles; human mesenchymal stem cells; intranasal delivery; stroke therapy

DOI: https://doi.org/10.1016/j.actbio.2026.02.049

Circulation. 2026 Mar 02.

Small Extracellular Vesicle External Surface Adiponectin-Mediated Adipocytes/Cardiomyocytes Communication in Diabetic Ischemic Heart Failure.

Zhen Zhang, Di Zhu, Caihong Liu, Lu Gan, Jianli Zhao, Zhijun Meng, Peng Yao, Demin Liu, Guoqiang Gu, Bernard Lopez, Theodore A Christopher, Yajing Wang, Xinliang Ma.

BACKGROUND: Mortality from acute myocardial infarction (MI) has declined significantly in the past decade for nondiabetic patients. However, both morbidity and mobility of ischemic heart failure (IHF) persistently escalate in the diabetic population via incompletely understood mechanisms. Recent studies demonstrated that small extracellular vesicles (sEVs) released from nondiabetic and diabetic adipocytes (ADps) exert opposite effects on acute myocardial ischemia and reperfusion (MI/R) injury. However, whether and how ADp sEVs may protect against post-MI remodeling and IHF, and more important, whether and how diabetes may impair this protective effect, remain unknown.
METHODS: sEVs were isolated from epididymal fat pads of nondiabetic animals and intramyocardially injected in nondiabetic or diabetic hearts subjected to MI (90 minutes of MI per 4 weeks of reperfusion).
RESULTS: sEV treatment significantly attenuated post-MI cardiac remodeling and improved cardiac function in nondiabetic mice. However, the protection was not observed in diabetic hearts. In adult cardiomyocytes isolated from nondiabetic hearts, sEVs rapidly (15 minutes) activated cell salvage kinases (ERK [extracellular signal-regulated kinase], AMPK [AMP-activated protein kinase], and ACC [acetyl-CoA carboxylase]) and suppressed oxidative stress-induced cell death, suggesting sEV external surface molecules are responsible for the observed cytoprotection. The Exo-Flow (a technology detecting sEV external surface molecules) demonstrated that adiponectin (APN) is enriched on the sEV external surface. The sEVs from APN knockout mice or APN neutralization (NU) antibody pretreated sEVs failed to protect the heart against IHF. Moreover, the cardioprotective effects of sEVs were abolished in APN receptor-1 (AdipoR1)-deficient mice (the primary receptor for APN signaling in the heart) or in mice overexpressing GRK2 (G-protein-coupled receptor kinase 2, a kinase that phosphorylates and inactivates AdipoR1). Finally, diabetes significantly increased cardiac GRK2 expression and AdipoR1 phosphorylation, which prevented sEVs from exerting their beneficial effects. Restoring AdipoR1 function by knockin a mutated phosphorylation-resistant AdipoR1 (AdipoR1S205A) via AAV9 (adeno-associated virus 9)-mediated gene delivery rescued ADp sEV cardioprotection in diabetic mice.
CONCLUSIONS: Our study reveals that APN is enriched on the ADp-derived external surface of sEVs and is biologically active, playing a critical role in ADp-cardiomyocyte communication. Diabetes disrupts this communication by enhancing GRK2-mediated AdipoR1 phosphorylation, impairing sEV signaling, and exacerbating IHF. These findings provide new insights into the pathophysiology and therapy of IHF in diabetes.

Keywords: adipocyte; adiponectin; diabetes; ischemic heart failure; small extracellular vesicle

DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.076372