The Vascular Biology and Regenerative Medicine Unit and the Clinical Research Unit of Regenerative Therapy work in synergy to develop strategies for the treatment of cardiac and peripheral vascular diseases, especially focusing on stem and progenitor cells as a tool for studying cardiovascular regeneration and modelling.
A special focus is given to cardiac and vascular pathologies with a genetic background. Basic molecular studies and experiments in animal models are complementary for the translation of new diagnostic and therapeutic strategies to patients.
Role of Cyclophilin A in genetic cardiovascular diseases
We are currently investigating the mechanisms by which Cyclophilin A (CyPA), – an ubiquitous immunophilin involved in the development of several cardiovascular diseases, – participates in the pathogenesis of two cardiovascular diseases of genetic origin namely Arrhythmogenic Cardiomyopathy (ACM) and Marfan syndrome (MFS).
- Effects of atrial fibrillation and statins on human cardiac progenitor cells (hCPC). We correlated the clinical profile of patients undergoing cardiac surgery with the biological features of hCPC obtained from right atrium surgical specimens, showing that a number of variables associated with patient's demographic and cardiologic status as well as medications, such as statins, influence resident hCPC number or functions.
- Role of hCPC on atrial fibrosis in atrial fibrillation. We are able to suggest a potential role for Atrial Fibrillation-derived cardiac progenitor cells (AF-CPC) in fibrosis process, which may explain the generation of an altered electric pattern in AF.
- SDF-1/CXCR4 axis protects from doxorubicin-induced cell death via acute activation of the p53/miR200c/Zeb1. Our study was aimed to identify new protective pathways able to reduce DOXO-induced cardiotoxicity, we focused on SDF1/CXCR4 axis that, when activated, protects heart against injury. We found that SDF1-treated mice were partially protected from DOXO-induced left ventricular adverse remodeling.
Regenerative effects of human cardiac mesenchymal progenitor cells (CmPC) in an in vivo model of myocardial infarction
We are currently studying the regenerative potential of both adult and pediatric CmPC after intramyocardial injection in a mouse model of myocardial infarction through permanent ligation of the left anterior descending coronary artery. We are evaluating CmPC effects on damaged murine hearts through echocardiographic, haemodynamic and histological analyses.
Arrhythmogenic Cardiomyopathy (ACM)
- Cardiac Mesenchymal Stromal Cells (C-MSC) are a source of adipocytes in ACM hearts. We identified a link of C-MSC adipogenesis with PKP2 and WNT pathway. Altogether, these data suggest that C-MSC are good candidates for ACM disease modeling.
- MiRNA-320 as a potential plasmatic biomarker of ACM. In order to evaluate whether microRNAs (miRNAs) expression levels allow a discrimination between ACM vs IVT patients, we adopted the random forest analysis considering non-invasive variables that can be used to distinguish the two populations. Our findings represent the proof of concept that plasmatic miRNAs could be exploited as potential non-invasive biomarkers of ACM diagnosis.
- Influence of Oxidized LDL (oxLDL) on Arrhythmogenic Cardiomyopathy (ACM) phenotype. Our results established that hyperlipidemia and oxidative stress are cofactors for accumulation of adipocytes in ACM hearts. Further studies on cell and mouse models of ACM will allow us to test novel therapeutic options for this category of patients.
Induced pluripotent stem cells (iPSC) in cardiovascular research
The discovery of iPSC technology revolutionized regenerative and personalized medicine. This technology enables us to take fully differentiated cells e.g. skin cells, and reprogram them into cells capable of differentiating into all cell types e.g. cardiomyocytes (CM). We routinely generate iPSC from patients’ dermal fibroblasts (skin cells) and characterize them for pluripotency (alkaline phosphatase activity, expression of pluripotency proteins; and CM differentiation ability (cardiac troponin T [cTnT2] and Nkx2.5 expression, and spontaneous electrical activity. There are several applications of iPSC technology for cardiovascular research which we explore in the project’s three active research lines:
- Modeling genetic cardiomyopathies using CM derived from iPSC (CM-d-iPSC)
- Drug screening in CM-d-iPSC
- Bioengineering strategies to improve CM-d-iPSC maturity
The Unit is involved in clinical studies on cell therapy for no-option cardiovascular ischemic disorders, including myocardial infarction complicated by ventricular dysfunction, refractory ischemic cardiomyopathy and untreatable limb ischemia. The overall aim is to investigate the potential effects of new therapies for patients with cardiovascular diseases that are not any more candidate to current state-of-the-art treatments.
- Sommariva E, Brambilla S, Carbucicchio C, Gambini E, Meraviglia V, Dello Russo A, Farina FM, Casella M, Catto V, Pontone G, Chiesa M, Stadiotti I, Cogliati E, Paolin A, Ouali Alami N, Preziuso C, d'Amati G, Colombo GI, Rossini A, Capogrossi MC, Tondo C, Pompilio G. Cardiac Mesenchymal Stromal Cells are a source of adipocytes in patients with Arrhythmogenic Right Ventricular Cardiomyopathy. Eur Heart J 2015;37(23):1835-1846.
- Achilli F, Malafronte C, Cesana F, Maggiolini S, Mauro C, De Ferrari GM, Lenatti L, Tespili M, Pasqualini P, Gentile F, Capogrossi MC, Maggioni A, Maseri A, Pontone G, Colombo GI, Pompilio G; STEM-AMI OUTCOME Trial Investigators. Granulocyte-colony stimulating factor for large anterior ST-elevation myocardial infarction: rationale and design of the prospective randomized phase III STEM-AMI OUTCOME trial. Am Heart J. 2015 Oct;170(4):652-658.e7.
- Pompilio G, Nigro P, Bassetti B, Capogrossi MC. Bone marrow cell therapy for ischemic heart disease: the never ending story. Circ Res 2015;117():490-493.
- Perrucci GL, Straino S, Corlianò M, Scopece A, Napolitano M, Berk BC, Pompilio G, Capogrossi MC, Nigro P. Cyclophilin A modulates bone-marrow derived CD117 positive cells and enhances the neo-angiogenic response to ischemia through SDF-1/CXCR4 axis. Int J Card 2016; 212:324-335.
- Bassetti B, Capogrossi MC, Pompilio G. Power is nothing without control: The enduring search for the best cell in cardiac cell therapy at a crossroads. Circ Res 2016; Epub ahead of print
Patrizia Nigro, Ph.D
Elisa Gambini, Ph.D - Tecnico
Maria Cristina Vinci, PhD
Alessandro Scopece, MSc - tecnico
Clinical Research Staff
Beatrice Bassetti, MSc - Assistente Clinico - Tecnico
Aoife Gowran, Ph.D
Giuseppina Milano, Ph.D
Gianluca Perrucci, Ph.D
Erica Rurali, Ph.D
Elena Sommariva, Ph.D
Chiara Pilato, MSc
Ilaria Stadiotti, MSc
Vera Vigorelli, MSc