The key role of miRNA in syndromic and sporadic forms of ascending aortic aneurysms as biomarkers and targets of novel therapeutic strategies.

Increasing evidence shows that epigenetics also plays a key role in regulating the pathogenetic mechanism of all types of aortic aneurysms. It is well-known that epigenetic factors modulate gene expression. This mechanism appears to be of interest especially knowing the relevance of genetic susceptibility and genetic factors in the complex pathophysiology of aortic aneurysms, and of sporadic forms; in fact, the latter are the result of a close interaction between genetic and modifiable lifestyle factors (i.e., nutrition, smoking, infections, use of drugs, alcohol, sedentary lifestyle, etc.). Epigenetic factors include DNA methylation, post-translational histone modifications, and non-coding RNA. Here, our attention is focused on the role of miRNA in syndromic and sporadic forms of thoracic aortic aneurysms. They could be both biomarkers and targets of novel therapeutic strategies.

miRNA Regulation of Cell Phenotype and Parietal Remodeling in Atherosclerotic and Non-Atherosclerotic Aortic Aneurysms: Differences and Similarities.

Aortic aneurysms are a serious health concern as their rupture leads to high morbidity and mortality. Abdominal aortic aneurysms (AAAs) and thoracic aortic aneurysms (TAAs) exhibit differences and similarities in their pathophysiological and pathogenetic features. AAA is a multifactorial disease, mainly associated with atherosclerosis, characterized by a relevant inflammatory response and calcification. TAA is rarely associated with atherosclerosis and in some cases is associated with genetic mutations such as Marfan syndrome (MFS) and bicuspid aortic valve (BAV). MFS-related and non-genetic or sporadic TAA share aortic degeneration with endothelial-to-mesenchymal transition (End-Mt) and fibrosis, whereas in BAV TAA, aortic degeneration with calcification prevails. microRNA (miRNAs) contribute to the regulation of aneurysmatic aortic remodeling. miRNAs are a class of non-coding RNAs, which post-transcriptionally regulate gene expression. In this review, we report the involvement of deregulated miRNAs in the different aortic remodeling characterizing AAAs and TAAs. In AAA, miRNA deregulation appears to be involved in parietal inflammatory response, smooth muscle cell (SMC) apoptosis and aortic wall calcification. In sporadic and MFS-related TAA, miRNA deregulation promotes End-Mt, SMC myofibroblastic phenotypic switching and fibrosis with glycosaminoglycan accumulation. In BAV TAA, miRNA deregulation sustains aortic calcification. Those differences may support the development of more personalized therapeutic approaches.

miR-632 Induces DNAJB6 Inhibition Stimulating Endothelial-to-Mesenchymal Transition and Fibrosis in Marfan Syndrome Aortopathy.

Marfan syndrome (MFS) is a connective tissue disorder caused by FBN1 gene mutations leading to TGF-ß signaling hyperactivation, vascular wall weakness, and thoracic aortic aneurysms (TAAs). The pathogenetic mechanisms are not completely understood and patients undergo early vascular surgery to prevent TAA ruptures. We previously reported miR-632 upregulation in MFS TAA tissues compared with non-genetic TAA tissues. DNAJB6 is a gene target of miR-632 in cancer and plays a critical role in blocking epithelial-to-mesenchymal transition by inhibiting the Wnt/ß catenin pathway. TGF-ß signaling also activates Wnt/ß catenin signaling and induces endothelial-to-mesenchymal transition (End-Mt) and fibrosis. We documented that miR-632 upregulation correlated with DNAJB6 expression in both the endothelium and the tunica media of MFS TAA (p < 0.01). Wnt/ß catenin signaling, End-Mt, and fibrosis markers were also upregulated in MFS TAA tissues (p < 0.05, p < 0.01 and p < 0.001). Moreover, miR-632 overexpression inhibited DNAJB6, inducing Wnt/ß catenin signaling, as well as End-Mt and fibrosis exacerbation (p < 0.05 and p < 0.01). TGF-ß1 treatment also determined miR-632 upregulation (p < 0.01 and p < 0.001), with the consequent activation of the aforementioned processes. Our study provides new insights about the pathogenetic mechanisms in MFS aortopathy. Moreover, the high disease specificity of miR-632 and DNAJB6 suggests new potential prognostic factors and/or therapeutic targets in the progression of MFS aortopathy.

The Endothelial Transcription Factor ERG Mediates a Differential Role in the Aneurysmatic Ascending Aorta with Bicuspid or Tricuspid Aorta Valve: A Preliminary Study.

The pathobiology of ascending aorta aneurysms (AAA) onset and progression is not well understood and only partially characterized. AAA are also complicated in case of bicuspid aorta valve (BAV) anatomy. There is emerging evidence about the crucial role of endothelium-related pathways, which show in AAA an altered expression and function. Here, we examined the involvement of ERG-related pathways in the differential progression of disease in aortic tissues from patients having a BAV or tricuspid aorta valve (TAV) with or without AAA. Our findings identified ERG as a novel endothelial-specific regulator of TGF-ß-SMAD, Notch, and NO pathways, by modulating a differential fibrotic or calcified AAA progression in BAV and TAV aortas. We provided evidence that calcification is correlated to different ERG expression (as gene and protein), which appears to be under control of Notch signaling. The latter, when increased, associated with an early calcification in aortas with BAV valve and aneurysmatic, was demonstrated to favor the progression versus severe complications, i.e., dissection or rupture. In TAV aneurysmatic aortas, ERG appeared to modulate fibrosis. Therefore, we proposed that ERG may represent a sensitive tissue biomarker to monitor AAA progression and a target to develop therapeutic strategies and influence surgical procedures.

Extracellular Vesicles and Cancer Stem Cells in Tumor Progression: New Therapeutic Perspectives.

Tumor burden is a complex microenvironment where different cell populations coexist and have intense cross-talk. Among them, a heterogeneous population of tumor cells with staminal features are grouped under the definition of cancer stem cells (CSCs). CSCs are also considered responsible for tumor progression, drug resistance, and disease relapse. Furthermore, CSCs secrete a wide variety of extracellular vesicles (EVs) with different cargos, including proteins, lipids, ssDNA, dsDNA, mRNA, siRNA, or miRNA. EVs are internalized by other cells, orienting the microenvironment toward a protumorigenic and prometastatic one. Given their importance in tumor growth and metastasis, EVs could be exploited as a new therapeutic target. The inhibition of biogenesis, release, or uptake of EVs could represent an efficacious strategy to impair the cross-talk between CSCs and other cells present in the tumor microenvironment. Moreover, natural or synthetic EVs could represent suitable carriers for drugs or bioactive molecules to target specific cell populations, including CSCs. This review will discuss the role of CSCs and EVs in tumor growth, progression, and metastasis and how they affect drug resistance and disease relapse. Furthermore, we will analyze the potential role of EVs as a target or vehicle of new therapies.

Mesenchymal Stem Cells in Adipose Tissue and Extracellular Vesicles in Ovarian Cancer Patients: A Bridge toward Metastatic Diffusion or a New Therapeutic Opportunity?

Ovarian cancer is one of the deadliest malignancies among women. Approximately 75% of the patients with ovarian cancer are diagnosed with advanced disease that already has metastasis, particularly to the omentum. The omentum constitutes the ideal soil for ovarian cancer metastasis due to a complex intraperitoneal milieu that favors and supports the whole metastatic process. Adipose-derived stem/stromal cells (ADSCs) are part of this microenvironment and foster tumor progression via sustained paracrine secretion, including extracellular vesicles (EVs). Nonetheless, the preferential relationship between ADSCs, ADSC-derived EVs, and ovarian cancer cells could be exploited to use ADSCs and EVs as a vehicle for anti-cancer therapies. This review will analyze the strict relations between tumor progression, metastatic disease, and adipose tissue with its staminal components. In addition, we will describe the crosstalk and biologic relationship between ADSCs and tumor cells, the role of EVs in intercellular communication, the establishment of drug resistance, metastatic capacity, and ovarian cancer progression. We will analyze the new therapeutic opportunities in treating ovarian cancer offered by ADSCs and EVs as a vehicle for therapeutic molecules to target precisely tumor cells and limit the systemic adverse effects. Finally, we will discuss the limitations of these therapeutic approaches.

Endothelial Progenitor Cell-Derived Extracellular Vesicles: Potential Therapeutic Application in Tissue Repair and Regeneration.

Recently, many studies investigated the role of a specific type of stem cell named the endothelial progenitor cell (EPC) in tissue regeneration and repair. EPCs represent a heterogeneous population of mononuclear cells resident in the adult bone marrow. EPCs can migrate and differentiate in injured sites or act in a paracrine way. Among the EPCs' secretome, extracellular vesicles (EVs) gained relevance due to their possible use for cell-free biological therapy. They are more biocompatible, less immunogenic, and present a lower oncological risk compared to cell-based options. EVs can efficiently pass the pulmonary filter and deliver to target tissues different molecules, such as micro-RNA, growth factors, cytokines, chemokines, and non-coding RNAs. Their effects are often analogous to their cellular counterparts, and EPC-derived EVs have been tested in vitro and on animal models to treat several medical conditions, including ischemic stroke, myocardial infarction, diabetes, and acute kidney injury. EPC-derived EVs have also been studied for bone, brain, and lung regeneration and as carriers for drug delivery. This review will discuss the pre-clinical evidence regarding EPC-derived EVs in the different disease models and regenerative settings. Moreover, we will discuss the translation of their use into clinical practice and the possible limitations of this process.