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Limana F.,Laboratorio Of Patologia Cellulare E Molecolare | Esposito G.,Laboratorio Of Patologia Vascolare | Fasanaro P.,Laboratorio Of Patologia Vascolare | Foglio E.,University of Rome La Sapienza | And 10 more authors.
Molecular Therapy | Year: 2013

Exogenous high-mobility group box 1 protein (HMGB1) administration to the mouse heart, during acute myocardial infarction (MI), results in cardiac regeneration via resident c-kit + cell (CPC) activation. Aim of the present study was to identify the molecular pathways involved in HMGB1-induced heart repair. Gene expression profiling was performed to identify differentially expressed genes in the infarcted and bordering regions of untreated and HMGB1-treated mouse hearts, 3 days after MI. Functional categorization of the transcripts, accomplished using Ingenuity Pathway Analysis software (IPA), revealed that genes involved in tissue regeneration, that is, cardiogenesis, vasculogenesis and angiogenesis, were present both in the infarcted area and in the peri-infarct zone; HMGB1 treatment further increased the expression of these genes. IPA revealed the involvement of Notch signaling pathways in HMGB1-treated hearts. Importantly, HMGB1 determined a 35 and 58% increase in cardiomyocytes and CPCs expressing Notch intracellular cytoplasmic domain, respectively. Further, Notch inhibition by systemic treatment with the γ-secretase inhibitor DAPT, which blocked the proteolytic activation of Notch receptors, reduced the number of CPCs, their proliferative fraction, and cardiomyogenic differentiation in HMGB1-treated infarcted hearts. The present study gives insight into the molecular processes involved in HMGB1-mediated cardiac regeneration and indicates Notch signaling as a key player. © The American Society of Gene & Cell Therapy.

Foglio E.,University of Rome La Sapienza | Puddighinu G.,University of Rome La Sapienza | Fasanaro P.,Epigenetics and Regenerative Pharmacology | D'Arcangelo D.,Laboratorio Of Patologia Vascolare | And 10 more authors.
International Journal of Cardiology | Year: 2015

Abstract Background We recently demonstrated that epicardial progenitor cells participate in the regenerative response to myocardial infarction (MI) and factors released in the pericardial fluid (PF) may play a key role in this process. Exosomes are secreted nanovesicles of endocytic origin, identified in most body fluids, which may contain molecules able to modulate a variety of cell functions. Here, we investigated whether exosomes are present in the PF and their potential role in cardiac repair. Methods and results Early gene expression studies in 3 day-infarcted mouse hearts showed that PF induces epithelial-to-mesenchymal transition (EMT) in epicardial cells. Exosomes were identified in PFs from non-infarcted patients (PFC) and patients with acute MI (PFMI). A shotgun proteomics analysis identified clusterin in exosomes isolated from PFMI but not from PFC. Notably, clusterin has a protective effect on cardiomyocytes after acute MI in vivo and is an important mediator of TGFβ-induced. Clusterin addition to the pericardial sac determined an increase in epicardial cells expressing the EMT marker α-SMA and, interestingly, an increase in the number of epicardial cells ckit+/α-SMA+, 7 days following MI. Importantly, clusterin treatment enhanced arteriolar length density and lowered apoptotic rates in the peri-infarct area. Hemodynamic studies demonstrated an improvement in cardiac function in clusterin-treated compared to untreated infarcted hearts. Conclusions Exosomes are present and detectable in the PFs. Clusterin was identified in PFMI-exosomes and might account for an improvement in myocardial performance following MI through a framework including EMT-mediated epicardial activation, arteriogenesis and reduced cardiomyocyte apoptosis. © 2015 Elsevier Ireland Ltd.

Germani A.,Laboratorio Of Patologia Vascolare | Foglio E.,University of Rome La Sapienza | Capogrossi M.C.,Laboratorio Of Patologia Vascolare | Russo M.A.,Laboratorio Of Patologia Cellulare E Molecolare | Limana F.,Laboratorio Of Patologia Cellulare E Molecolare
Journal of Molecular Medicine | Year: 2015

The epithelial to mesenchymal transition (EMT) is a biological process that drives the formation of cells involved both in tissue repair and in pathological conditions, including tissue fibrosis and tumor metastasis by providing cancer cells with stem cell properties. Recent findings suggest that EMT is reactivated in the heart following ischemic injury. Specifically, epicardial EMT might be involved in the formation of cardiac progenitor cells (CPCs) that can differentiate into endothelial cells, smooth muscle cells, and, possibly, cardiomyocytes. The identification of mechanisms and signaling pathways governing EMT-derived CPC generation and differentiation may contribute to the development of a more efficient regenerative approach for adult heart repair. Here, we summarize key literature in the field. © 2015, Springer-Verlag Berlin Heidelberg.

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