Unit of Vascular Biology and Regenerative Medicine

Translational Research

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).

Cardiac progenitors

• 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

Clinical Research

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.

• Sforza A, Vigorelli V, Rurali E, Perrucci GL, Gambini E, Arici M, Metallo A, Rinaldi R, Fiorina P, Barbuti A, Raucci A, Sacco E, Rocchetti M, Pompilio G, Genovese S, Vinci MC. Cardiovasc Diabetol. 2022 Apr 9;21(1):51. doi: 10.1186/s12933-022-01486-9.PMID: 35397526. Liraglutide preserves CD34⁺ stem cells from dysfunction Induced by high glucose exposure.
• Sommariva E, Stadiotti I, Casella M, Catto V, Dello Russo A, Carbucicchio C, Arnaboldi L, De Metrio S, Milano G, Scopece A, Casaburo M, Andreini D, Mushtaq S, Conte E, Chiesa M, Birchmeier W, Cogliati E, Paolin A, König E, Meraviglia V, De Musso M, Volani C, Cattelan G, Rauhe W, Turnu L, Porro B, Pedrazzini M, Camera M, Corsini A, Tondo C, Rossini A, Pompilio G. EMBO Mol Med. 2021 Sep 7;13(9):e14365. doi: 10.15252/emmm.202114365. PMID: 34337880. Oxidized LDL-dependent pathway as new pathogenic trigger in arrhythmogenic cardiomyopathy.
• Bulfamante GP, Perrucci GL, Falleni M, Sommariva E, Tosi D, Martinelli C, Songia P, Poggio P, Carugo S, Pompilio G. Biomedicines. 2020 Dec 18;8(12):626. doi: 10.3390/biomedicines8120626.PMID: 33352880. Evidence of SARS-CoV-2 Transcriptional Activity in Cardiomyocytes of COVID-19 Patients without Clinical Signs of Cardiac Involvement.
• Rovina D, Castiglioni E, Niro F, Farini A, Belicchi M, Di Fede E, Gervasini C, Paganini S, Di Segni M, Torrente Y, Santoro R, Pompilio G, Gowran A. Stem Cell Res. 2020 May;45:101819. doi: 10.1016/j.scr.2020.101819. PMID: 32348941. Generation of the Becker muscular dystrophy patient derived induced pluripotent stem cell line carrying the DMD splicing mutation c.1705-8 T>C.
• Perrucci GL, Rurali E, Corlianò M, Balzo M, Piccoli M, Moschetta D, Pini A, Gaetano R, Antona C, Egea G, Fischer G, Malešević M, Alamanni F, Cogliati E, Paolin A, Pompilio G, Nigro P. Cells. 2020 Jan 8;9(1):154. doi: 10.3390/cells9010154.PMID: 31936351. Cyclophilin A/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients.

Giulio Pompilio, MD, PhD

Elena Sommariva, PhD

Maria Cristina Vinci, PhD

Rosaria Santoro, PhD

Gianluca Lorenzo Perrucci, PhD

Erica Rurali, PhD

Angela Serena Maione, PhD

Davide Rovina, PhD

Martina Rabino, PhD

Daniela Lorizio, PhD

Melania Lippi, PhD student

Alessandro Scopece, MSc

Sara Mallia, MSc

Sara Rega, MSc

Lara Iengo, MSc

Giulia Damiano, MSc

Raffaella Rinaldi, MSc