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ASEMV 2019 Annual Meeting on Exosomes & Microvesicles—Day 4, Wednesday, October 9

Wednesday’s sessions of the annual ASEMV 2019 meeting at Asilomar,in Pacific Grove, California, featured multiple exciting presentations. Among the 19 talks of the day, we will focus on five of particular interest. Luis Rodriguez-Borlado, PhD, of Capricor Therapeutics, delivered as presentation titled “Extracellular Vesicles from Cardiosphere-Derived Cells (CDCs) Are Taken Up by Muscle Stem Cells and Increase Exercise Capability in a Duchenne Muscular Dystrophy Model.” Dr. Rodriguez-Borlada introduced his discussion by stating that Duchenne muscular dystrophy (DMD) patients infused with CDCs showed an improvement in PUL (pullulanase) activity, skeletal muscle activity, and a reduction in myocardial scarring when compared to placebo-treated patients. He noted that there is wide acceptance that most of the therapeutic effects observed in cell therapies using non-engrafting cells are caused by paracrine factors secreted by the delivered cells. In the current work, Dr. Rodriguez-Borlado said his group observed significant improvement in exercise capability in mdx mice (DMD model mice) treated wit CDC-EVs when compared with control-treated mice. EVs from immortal CDCs also showed immunomodulatory capabilities on macrophages and improved exercise capability in mdx mice, opening the possibility of developing consistent, robust, and affordable manufacturing process for producing clinical-grade EVs. Julia Saugstad, PhD, Oregon Health & Science University, presented work by a collaborative group and the presentation was titled “Establishing the Contributions of Extracellular miRNAs to Alzheimer’s Disease.” As background, Dr. Saugstad said that Alzheimer’s disease (AD) is the most common form of dementia, the sixth leading cause of death in the United States, and fifth-leading cause of death in those age 65 and older. Currently, available biomarkers for AD are limited. In the current work, Dr. Saugstad reports her group’s discovering and validating miRNAs in cerebrospinal fluid (CSF) that discriminate patients with AD from neurologically normal controls. She added that combining subsets of miRNAs improves sensitivity and specificity of biomarker performance, and adding ApoE4 genotype or A-beta42:total tau ratio measures to miRNA multimarker models improves classification performance. She further noted that EVs and their miRNA cargo reveal important information regarding mechanisms underlying AD pathology, and reveal that sex and ApoE4 genotype may contribute to the predisposition for AD in females versus males.

EXOSOSOMS AND COPD

Derek Russell, PhD, University of Alabama-Birmingham, gave a presentation titled “The NE+ Neutrophil Exosome Is a Promising Therapeutic Target in a Mouse Model of COPD.” Dr. Russell began by stating that chronic obstructive pulmonary disease (COPD) is characterized by lung extracellular matrix (ECM) remodeling that contributes to obstruction. This is driven, in part, by exosomes from activated neutrophils (PMNs), which express an a-1 antitrypsin (AAT) insensitive form of neutrophil elastase (NE). Such exosomes bind to pulmonary ECM components such as type I collagen, via exosome-surface expression of the integrin Mac-1. Protamine sulfate is a cationic compound used safely for decades in humans. In vitro, the NE upon exosomes is dissociated from the exosome surface by protamine-sulfate, rendering the NE AAT-sensitive. MP-9 is a nonapeptide inhibitor of the binding site of Mac-1. Dr.Russell and colleagues sought to prevent NE+ exosome-driven ECM remodeling in an animal COPD model. In conclusion, Dr. Russell said that activated PMN exosomes cause a COPD-like phenotype when given intrathechally to mice. Protamine sulfate and MP-9 each disrupt a key facet of NE+ exosome pathogenicity (AAT resistance and ECM binding, respectively). Exosome-mediated alveolar destruction is attenuated when exosmes are preincubated with either of these agents, and completely ameliorated when preincubated with both agents. This, Dr. Russell said, provides proof of principle that therapeutic strategies designed to disrupt pathogenic exosome characteristics can avert ECM damage in vivo. Such therapies might be tailored into promising disease-modifying COPD treatment and related ailments.

EXO-ALIX AND ORAL SQUAMOUS CELL CARCIONOMA

Eiji Nakamachi, PhD, of Nagoya University in Japan, gave a presentation titled “Exosome-Associated Protein Alix As a Novel Diagnostic Marker for Oral Squamous Cell Carcinoma.” Dr. Nakamchi began by noting that oral squamous cell carcinoma (OSCC) is the most common form of oral cancer. The 5-year survival rate for stage I OSCC is reported to be 80%, while just 30-50% for stage III or IV OSCC. Carcinoembryonic antigen (CEA) and squamous cell carcinoma (SCC) antigen are used as markers for OSCC, but only 10% of patients with stage I OSCC test positive for these markers. Programmed cell death 6-interactin protein (Alix), present within exosomes, has been reported to be involved in tumor cell proliferation; however, the role of Alix in OSCC is not yet clear. In the current study, Dr. Nakamachi and colleagues determined the expression of exosomal Alix (exo-Alix) in the exosomes isolated from the serum and saliva of OSCC patients and examined the potential of exo-Alix as a novel diagnostic marker for OSCC. In the work, immunostaining confirmed that Alix was expressed in resected tumor samples. In addition, the serum and saliva levels of exo-Alix were significantly higher in the OSCC group than in the control group. Further, the serum exo-Alix concentration was significantly high in stage III OSCC patients. The group concluded that their study suggests that exo-Alix levels in the serum and saliva samples can be used as a diagnostic marker for OSCC.

EXOSOMES AND DIABTES

Robert Raffai, PhD, of the University of California-San Francisco (UCSF), delivered a presentation titled “Macrophage-Exosomes Control Hematopoiesis & Inflammation in Diabetes.” Dr. Raffai gave an introduction in which he noted that diabetes is recognized to enhance the frequency and severity of atherosclerosis and cardiovascular disease. He said that recent studies have shown that hyperglycemia is associated with enhanced hematopoiesis and macrophage accumulation in atherosclerotic lesions. In the current work, his group investigated whether high glucose concentrations can enhance intercellular communication between mature macrophages and hematopoietic progenetors via exosomes to promote inflammation and diabetes. The Raffai group concluded that exosomes derived from cultured bone-marrow-derived macrophages (BMDM) exposed to high glucose display a capacity to exert inflammatory intercellular communication in vitro and in vivo. These findings suggest, Dr. Raffai said, that exosomes produced by macrophages exposed to hyperglycemia might represent an unsuspected source of inflammation to accelerate atherosclerosis in diabetes.