Elisa Gambini | Centro Cardiologico Monzino (original) (raw)

Papers by Elisa Gambini

$Research paper thumbnail of Emerging Treatment Options for Refractory Angina Pectoris: Ranolazine, Shock Wave Treatment, and Cell-Based Therapies$

Reviews in Cardiovascular Medicine, 2014

A challenge of modern cardiovascular medicine is to find new, effective treatments for patients w... more A challenge of modern cardiovascular medicine is to find new, effective treatments for patients with refractory angina pectoris, a clinical condition characterized by severe angina despite optimal medical therapy. These patients are not candidates for surgical or percutaneous revascularization. Herein we review the most up-to-date information regarding the modern approach to the patient with refractory angina pectoris, from conventional medical management to new medications and shock wave therapy, focusing on the use of endothelial precursor cells (EPCs) in the treatment of this condition. Clinical limitations of the efficiency of conventional approaches justify the search for new therapeutic options. Regenerative medicine is considered the next step in the evolution of organ replacement therapy. It is driven largely by the same health needs as transplantation and replacement therapies, but it aims further than traditional approaches, such as cell-based therapy. Increasing knowledge of the role of circulating cells derived from bone marrow (EPCs) on cardiovascular homeostasis in physiologic and pathologic conditions has prompted the clinical use of these cells to relieve ischemia. The current state of therapeutic angiogenesis still leaves many questions unanswered. It is of paramount importance that the treatment is delivered safely. Direct intramyocardial and intracoronary administration has demonstrated acceptable safety profiles in early trials, and may represent a major advance over surgical thoracotomy. The combined efforts of bench and clinical researchers will ultimately answer the question of whether cell therapy is a suitable strategy for treatment of patients with refractory angina.

This record contains raw data related to the article "Differences in Mitochondrial Membrane ... more This record contains raw data related to the article "Differences in Mitochondrial Membrane Potential Identify Distinct Populations of Human Cardiac Mesenchymal Progenitor Cells". Adult human cardiac mesenchymal progenitor cells (hCmPC) are multipotent resident populations involved in cardiac homeostasis and heart repair<strong>. </strong>Even if the mechanisms have not yet been fully elucidated, the stem cell differentiation is guided by the mitochondrial metabolism; however, mitochondrial approaches to identify hCmPC with enhanced stemness and/or differentiation capability for cellular therapy are not established. Here we demonstrated that hCmPCs sorted for low and high mitochondrial membrane potential (using a lipophilic cationic dye tetramethylrhodamine methyl ester, TMRM), presented differences in energy metabolism from preferential glycolysis to oxidative rates. TMRM-high cells are highly efficient in terms of oxygen consumption rate, basal and maximal re...

Background: Glucagon like peptide-1 receptor agonists (GLP-1RAs) have shown to reduce mortality a... more Background: Glucagon like peptide-1 receptor agonists (GLP-1RAs) have shown to reduce mortality and cardiovascular events in patients with type 2 diabetes mellitus (T2DM). Since the impairment in number and function of vasculotrophic circulating CD34+ hematopoietic stem progenitor cells (HSPCs) in T2D has been reported to increase cardiovascular (CV) risk, we hypothesized that one of the mechanisms whereby GLP-1 RAs exert CV protective effects may be related to the ability to improve CD34+ HSPC function.Methods: In cord blood (CB)-derived CD34+ HSPC, the expression of GLP-1 receptor (GLP-1R) mRNA, receptor protein and intracellular signaling was evaluated by RT-qPCR and by Western Blot respectively. CD34+ HSPCs were exposed to high glucose (HG) condition and GLP-1RA liraglutide (LIRA) was added before as well as after functional impairment. Proliferation, CXCR4/SDF-1α axis activity and intracellular ROS production of CD34+ HSPC were evaluated. Results: CD34+ HSPCs express GLP-1R at ...

BMC Biology, 2021

Background Doxorubicin (Dox) is an anti-cancer anthracycline drug that causes double-stranded DNA... more Background Doxorubicin (Dox) is an anti-cancer anthracycline drug that causes double-stranded DNA breaks. It is highly effective against several types of tumours; however, it also has adverse effects on regenerative populations of normal cells, such as human cardiac mesenchymal progenitor cells (hCmPCs), and its clinical use is limited by cardiotoxicity. Another known effect of Dox is nucleolar disruption, which triggers the ubiquitously expressed nucleolar phosphoprotein Nucleophosmin (NPM) to be released from the nucleolus into the cell, where it participates in the orchestration of cellular stress responses. NPM has also been observed in the extracellular space in response to different stress stimuli; however, the mechanism behind this and its functional implications are as yet largely unexplored. The aim of this study was to establish whether Dox could elicit NPM secretion in the extracellular space and to elucidate the mechanism of secretion and the effect of extracellular NPM ...

International Journal of Molecular Sciences, 2020

Diabetes strongly contributes to the development of cardiovascular disease, the leading cause of ... more Diabetes strongly contributes to the development of cardiovascular disease, the leading cause of mortality and morbidity in these patients. It is widely accepted that hyperglycemia impairs hematopoietic stem/progenitor cell (HSPC) mobilization from the bone marrow (BM) by inducing stem cell niche dysfunction. Moreover, a recent study demonstrated that type 2 diabetic patients are characterized by significant depletion of circulating provascular progenitor cells and increased frequency of inflammatory cells. This unbalance, potentially responsible for the reduction of intrinsic vascular homeostatic capacity and for the establishment of a low-grade inflammatory status, suggests that bone BM-derived HSPCs are not only victims but also active perpetrators in diabetic complications. In this review, we will discuss the most recent literature on the molecular mechanisms underpinning hyperglycemia-mediated BM dysfunction and differentiation abnormality of HSPCs. Moreover, a section will be ...

Current Stem Cell Research & Therapy, 2020

Nowadays, cardiac regeneration is an emerging topic in the cardiovascular field because of the co... more Nowadays, cardiac regeneration is an emerging topic in the cardiovascular field because of the compelling need for effective therapies for repairing or replacing cardiac tissue damaged by pathological or physiological conditions. Indeed, irreversible myocardial remodeling which follows acute myocardial infarction represents a serious burden of this century. In this context, a great improvement in pharmacological and interventional techniques is accompanied by a big challenge of cardiac regenerative medicine. In the last 20 years, several clinical trials tried to investigate the role of different types of stem cells in promoting cardiac repair. However, the promising results obtained in the preclinical trials have not yet been reproduced in patients. Thus, the development of novel strategies to improve stem cell efficiency became imperative. Here, an overview of the more recent cell types proposed for cardiac regeneration is presented, together with the most interesting approaches to...

$Research paper thumbnail of Linking cell function with perfusion: insights from the transcatheter delivery of bone marrow-derived CD133+ cells in ischemic refractory cardiomyopathy trial (RECARDIO)$

Stem Cell Research & Therapy, 2018

Background: Cell therapy with bone marrow (BM)-derived progenitors has emerged as a promising the... more Background: Cell therapy with bone marrow (BM)-derived progenitors has emerged as a promising therapeutic for refractory angina (RA) patients. In the present study, we evaluated the safety and preliminary efficacy of transcatheter delivery of autologous BM-derived advanced therapy medicinal product CD133 + cells (ATMP-CD133) in RA patients, correlating perfusion outcome with cell function. Methods: In the phase I "Endocavitary Injection of Bone Marrow Derived CD133 + Cells in Ischemic Refractory Cardiomyopathy" (RECARDIO) trial, a total of 10 patients with left ventricular (LV) dysfunction (ejection fraction ≤ 45%) and evidence of reversible ischemia, as assessed by single-photon emission computed tomography (SPECT), underwent BM aspiration and fluoroscopy-based percutaneous endomyocardial delivery of ATMP-CD133. Patients were evaluated at 6 and 12 months for safety and preliminary efficacy endpoints. ATMP-CD133 samples were used for in vitro correlations. Results: Patients were treated safely with a mean number of 6.57 ± 3.45 × 10 6 ATMP-CD133. At 6-month follow-up, myocardial perfusion at SPECT was significantly ameliorated in terms of changes in summed stress (from 18.2 ± 8.6 to 13.8 ± 7.8, p = 0.05) and difference scores (from 12.0 ± 5.3 to 6.1 ± 4.0, p = 0.02) and number of segments with inducible ischemia (from 7.3 ± 2.2 to 4.0 ± 2.7, p = 0.003). Similarly, Canadian Cardiovascular Society and New York Heart Association classes significantly improved at follow-up vs baseline (p ≤ 0.001 and p = 0.007, respectively). Changes in summed stress score changes positively correlated with ATMP-CD133 release of proangiogenic cytokines HGF and PDGF-bb (r = 0.80, p = 0.009 and r = 0.77, p = 0.01, respectively) and negatively with the proinflammatory cytokines RANTES (r = − 0.79, p = 0.01) and IL-6 (r = − 0.76, p = 0.02).

Translational research : the journal of laboratory and clinical medicine, Feb 1, 2018

Atrial fibrillation (AF) is characterized by electrical, contractile, and structural remodeling m... more Atrial fibrillation (AF) is characterized by electrical, contractile, and structural remodeling mediated by interstitial fibrosis. It has been shown that human cardiac mesenchymal progenitor cells (CMPCs) can be differentiated into endothelial, smooth muscle, and fibroblast cells. Here, we have investigated, for the first time, the contribution of CMPCs in the fibrotic process occurring in AF. As expected, right auricolae samples displayed significantly higher fibrosis in AF vs control (CTR) patients. In tissue samples of AF patients only, double staining for c-kit and the myofibroblast marker α-smooth muscle actin (α-SMA) was detected. The number of c-kit-positive CMPC was higher in atrial subepicardial regions of CTR than AF cells. AF-derived CMPC (AF-CMPC) and CTR-derived CMPC (Ctr-CMPC) were phenotypically similar, except for CD90 and c-kit, which were significantly more present in AF and CTR cells, respectively. Moreover, AF showed a lower rate of population doubling and fold e...

Cardiovascular Research, 2016

Introduction: Advances in diagnosis and therapy have made cancer curable in a substantial proport... more Introduction: Advances in diagnosis and therapy have made cancer curable in a substantial proportion of patients. As a consequence, long-term side effects of oncological drugs, such as anthracyclines, may become the major health problem in cancer survivors. Chemotherapy-derived cardiotoxicity is a chronic complication with a dramatically relevant clinical impact in the development of late onset cardiomyopathy. Unfortunately, no truly effective way to prevent anthracycline cardiotoxicity currently exists. Recent work has identified human AFS (hAFS) and their conditioned medium (hAFS-CM) as a novel tool to significantly reduce myocardial infarct damage. Purpose: The aim of this study is to validate the cardioprotective potential of the hAFS secretome in a doxorubicin (Dox)-derived cardiotoxicity model in vitro. Methods: c-kit+ hAFS were isolated from left over samples of II trimester amniotic fluid diagnostic amniocenteses with normal karyotype, following informed consent. Cells were cultured for 24h without serum in normoxia (20% O2) or hypoxia (1% O2) to enrich the hAFS-CM with cardioactive factors. The cardioprotective potential of the hAFS-CM on Dox-induced senescence and apoptosis was assessed on rat H9c2 cardiomyoblasts, primary mouse neonatal cardiomyocytes (mNVCM) and human c-kit+ cardiac progenitor cells. Senescence was evaluated by staining for b-galactosidase and p16INK4a, whereas apoptosis was assessed by cleaved caspase-3 expression. The activation of the DNA damage response (DDR) was measured by gH2AX immunostaining. Gene expression profiling was performed to identify pathways activated by the hAFS-CM. The role of PI3K/Akt signaling was investigated by western blot and via functional experiments using the PI3K inhibitor LY294002. Results: Both Dox-induced senescence and apoptosis were considerably antagonized by the hAFS-CM, in particular by the hypoxic hAFS-CM (hAFS-CMHypo). The hAFS-CMHypo also limited the DDR activation by Dox in mNVCM. Gene expression analysis on treated mNVCM revealed substantial up-regulation of pro-survival cytokines, such as Il6 and Cxcl1 and of the Abcb1b gene, encoding for a protein involved in Dox efflux. Akt phosphorylation was promptly activated by the hAFS-CMHypo, while LY294002 prevented its beneficial effect in counteracting Dox-triggered senescence and apoptosis. Conclusions: The paracrine potential of the hAFS secretome protects cardiomyocytes and cardiac progenitor cells against doxorubicin negative side effects, suggesting a novel therapeutic strategy to tackle the cardiotoxicity of anthracyclines during oncological therapy.

Cell death & disease, Jan 24, 2017

Doxorubicin (DOXO) treatment is limited by its cardiotoxicity, since it causes cardiac-progenitor... more Doxorubicin (DOXO) treatment is limited by its cardiotoxicity, since it causes cardiac-progenitor-cell depletion. Although the cardioprotective role of the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 (SDF1/CXCR4) axis is well established, its involvement during DOXO-induced cardiotoxicity has never been investigated. We showed that in a mouse model of DOXO-induced cardiomyopathy, CXCR4(+) cells were increased in response to DOXO, mainly in human cardiac mesenchymal progenitor cells (CmPC), a subpopulation with regenerative potential. Our in vitro results showed a CXCR4 induction after 24 h of DOXO exposure in CmPC. SDF1 administration protected from DOXO-induced cell death and promoted CmPC migration. CXCR4 promoter analysis revealed zinc finger E-box binding homeobox 1 (ZEB1) binding sites. Upon DOXO treatment, ZEB1 binding decreased and RNA-polymerase-II increased, suggesting a DOXO-mediated transcriptional increase in CXCR4. Indeed, DOXO induced the upregulation...

Journal of Cellular and Molecular Medicine, 2016

The recruitment of bone marrow (BM)-derived progenitor cells to the lung is related to pulmonary ... more The recruitment of bone marrow (BM)-derived progenitor cells to the lung is related to pulmonary remodelling and the pathogenesis of pulmonary hypertension (PH). Although sildenafil is a known target in PH treatment, the underlying molecular mechanism is still elusive. To test the hypothesis that the therapeutic effect of sildenafil is linked to the reduced recruitment of BM-derived progenitor cells, we induced pulmonary remodelling in rats by two-week exposure to chronic hypoxia (CH, 10% oxygen), a trigger of BM-derived progenitor cells. Rats were treated with either placebo (saline) or sildenafil (1.4 mg/kg/day ip) during CH. Control rats were kept in room air (21% oxygen) with no treatment. As expected, sildenafil attenuated the CH-induced increase in right ventricular systolic pressure and right ventricular hypertrophy. However, sildenafil suppressed the CH-induced increase in c-kit+ cells in the adventitia of pulmonary arteries. Moreover, sildenafil reduced the number of c-kit+ cells that colocalize with tyrosine kinase receptor 2 (VEGF-R2) and CD68 (a marker for macrophages), indicating a positive effect on moderating hypoxia-induced smooth muscle cell proliferation and inflammation without affecting the pulmonary levels of hypoxia-inducible factor (HIF)-1. Furthermore, sildenafil depressed the number of CXCR4+ cells. Collectively, these findings indicate that the improvement in pulmonary haemodynamic by sildenafil is linked to decreased recruitment of BM-derived c-kit+ cells in the pulmonary tissue. The attenuation of the recruitment of BM-derived c-kit+ cells by sildenafil may provide novel therapeutic insights into the control of pulmonary remodelling.

Mechanisms of Ageing and Development, 2016

The bone marrow (BM) is a well-recognized source of stem/progenitor cells for cell therapy in car... more The bone marrow (BM) is a well-recognized source of stem/progenitor cells for cell therapy in cardiovascular diseases (CVDs). Preclinical and clinical studies suggest that endothelial progenitor cells (EPCs) contribute to reparative process of vascular endothelium and participate in angiogenesis. As for all organs and cells across the lifespan, BM and EPCs are negatively impacted by ageing due to microenvironment modifications and EPC progressive dysfunctions. The encouraging results in terms of neovascularization observed in young animals after EPC administration were mitigated in aged patients treated for ischemic CVDs. The limited efficacy of EPC-based therapy in clinical setting might be ascribed at least partly to ageing. In this review, we comprehensively discussed the age-related changes of BM and EPCs and their implication for cardiovascular cell-therapies. Finally, we examined alternative approaches under investigation to enhance EPC potency.

Scientific Reports, 2016

The anthracycline doxorubicin (Dox) is widely used in oncology, but it may cause a cardiomyopathy... more The anthracycline doxorubicin (Dox) is widely used in oncology, but it may cause a cardiomyopathy with bleak prognosis that cannot be effectively prevented. The secretome of human amniotic fluid-derived stem cells (hAFS) has previously been demonstrated to significantly reduce ischemic cardiac damage. Here it is shown that, following hypoxic preconditioning, hAFS conditioned medium (hAFS-CM) antagonizes senescence and apoptosis of cardiomyocytes and cardiac progenitor cells, two major features of Dox cardiotoxicity. Mechanistic studies with mouse neonatal ventricular cardiomyocytes (mNVCM) reveal that hAFS-CM inhibition of Dox-elicited senescence and apoptosis is associated with decreased DNA damage, nuclear translocation of NF-kB and upregulation of the NF-kB controlled genes, Il6 and Cxcl1, promoting mNVCM survival. Furthermore, hAFS-CM induces expression of the efflux transporter, Abcb1b and Dox extrusion from mNVCM. The PI3K/Akt signaling cascade, upstream of NF-kB, is potently ...

Current Stem Cell Research & Therapy, 2016

Epigenetics harbours all regulatory information that, beyond nucleotide sequences, allows cells t... more Epigenetics harbours all regulatory information that, beyond nucleotide sequences, allows cells to "make decisions" throughout their lifetime in response to the external environment. The information can be transitory or relatively stable, and is even transmittable either to daughter cells or to the next generations through the germ line. Recent discoveries shed light on numerous connections between metabolites and epigenetic chromatin-modifying enzymes, providing a link between the metabolic state of the cell and epigenetics, and ultimately between metabolism, gene expression and cell fate. In this review, we discuss the possible connections between metabolism and epigenetic regulation of stem cell differentiation and self-renewal. Moreover, we describe pertinent literature that could explain how altered metabolic state and nutrition can contribute to disease development through epigenetic modifications. A special section is dedicated to the emerging link between the circadian clock, metabolic transcriptional regulation by epigenetic mechanisms and their implication in stem cell homeostasis.

Circulation, Nov 23, 2010

Circulation, Nov 26, 2013

European Heart Journal, 2015

Aim Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder mainly due to mutations in desmosom... more Aim Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder mainly due to mutations in desmosomal genes, characterized by progressive fibro-adipose replacement of the myocardium, arrhythmias, and sudden death. It is still unclear which cell type is responsible for fibro-adipose substitution and which molecular mechanisms lead to this structural change. Cardiac mesenchymal stromal cells (C-MSC) are the most abundant cells in the heart, with propensity to differentiate into several cell types, including adipocytes, and their role in ACM is unknown. The aim of the present study was to investigate whether C-MSC contributed to excess adipocytes in patients with ACM. Methods and results We found that, in ACM patients' explanted heart sections, cells actively differentiating into adipocytes are of mesenchymal origin. Therefore, we isolated C-MSC from endomyocardial biopsies of ACM and from not affected by arrhythmogenic cardiomyopathy (NON-ACM) (control) patients. We found that both ACM and control C-MSC express desmosomal genes, with ACM C-MSC showing lower expression of plakophilin (PKP2) protein vs. controls. Arrhythmogenic cardiomyopathy C-MSC cultured in adipogenic medium accumulated more lipid droplets than controls. Accordingly, the expression of adipogenic genes was higher in ACM vs. NON-ACM C-MSC, while expression of cell cycle and anti-adipogenic genes was lower. Both lipid accumulation and transcription reprogramming were dependent on PKP2 deficiency. Conclusions Cardiac mesenchymal stromal cells contribute to the adipogenic substitution observed in ACM patients' hearts. Moreover, C-MSC from ACM patients recapitulate the features of ACM adipogenesis, representing a novel, scalable, patientspecific in vitro tool for future mechanistic studies.

Pharmacology & Therapeutics, 2011

Preclinical studies performed in cell culture and animal systems have shown the outstanding abili... more Preclinical studies performed in cell culture and animal systems have shown the outstanding ability of stem cells to repair ischemic heart and lower limbs by promoting the formation of new blood vessels and new myocytes. In contrast, clinical studies of stem cell administration in patients with myocardial ischemia have revealed only modest, although promising, results. Basic investigations have shown the feasibility of adult cells reprogramming into pluripotent cells by defined factors, thus opening the way to the devise of protocols to ex vivo derive virtually unexhausted cellular pools. In contrast, cellular and molecular studies have indicated that risk factors limit adult-derived stem cell survival, proliferation and engraftment in ischemic tissues. The use of fully reprogrammed cells raises safety concerns; therefore, adult cells remain a primary option for clinicians interested in therapeutic cardiovascular repair. Pharmacologic approaches have been devised to restore the cardiovascular repair ability of failing progenitors from patients at risk. In the present contribution, the most advanced pharmacologic approaches to (re)program, boost, and condition endothelial and cardiac progenitor cells to enhance cardiovascular regeneration are discussed.

Clinical Biochemistry, 2013