Publications by authors named "Isotta Chimenti"

60 Publications

Impact of chronic use of heat-not-burn cigarettes on oxidative stress, endothelial dysfunction and platelet activation: the SUR-VAPES Chronic Study.

Thorax 2021 06 19;76(6):618-620. Epub 2021 Apr 19.

IRCCS NeuroMed, Pozzilli, Italy.

Tobacco habit still represents the leading preventable cause of morbidity and mortality worldwide. Heat-not-burn cigarettes (HNBCs) are considered as an alternative to traditional combustion cigarettes (TCCs) due to the lack of combustion and the absence of combustion-related specific toxicants. The aim of this observational study was to assess the effect of HNBC on endothelial function, oxidative stress and platelet activation in chronic adult TCC smokers and HNBC users. The results showed that both HNBC and TCC display an adverse phenotype in terms of endothelial function, oxidative stress and platelet activation. Future randomised studies are strongly warranted to confirm these data.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215900DOI Listing
June 2021

Inhibition of miR-155 Attenuates Detrimental Vascular Effects of Tobacco Cigarette Smoking.

J Am Heart Assoc 2020 12 2;9(24):e017000. Epub 2020 Dec 2.

Department of Medical-Surgical Sciences and Biotechnologies Sapienza University of Rome Latina Italy.

Background The role of microRNAs dysregulation in tobacco cigarette smoking-induced vascular damage still needs to be clarified. We assessed the acute effects of tobacco cigarette smoking on endothelial cell-related circulating microRNAs in healthy subjects. In addition, we investigated the potential role of microRNAs in smoking-dependent endothelial cell damage. Methods and Results A panel of endothelial-related microRNAs was quantified in healthy subjects before and after smoking 1 tobacco cigarette. Serum levels of miR-155 were found to be significantly increased shortly after smoking. We also observed a progressive and significant miR-155 accumulation in culture media of human endothelial cells after 30 minutes and up to 4 hours of cigarette smoke condensate treatment in vitro without evidence of cell death, indicating that miR-155 can be released by endothelial cells in response to smoking stress. Cigarette smoke condensate appeared to enhance oxidative stress and impair cell survival, angiogenesis, and NO metabolism in human endothelial cells. Notably, these effects were abrogated by miR-155 inhibition. We also observed that miR-155 inhibition rescued the deleterious effects of cigarette smoke condensate on endothelial-mediated vascular relaxation and oxidative stress in isolated mouse mesenteric arteries. Finally, we found that exogenous miR-155 overexpression mimics the effects of smoking stress by inducing the upregulation of inflammatory markers, impairing angiogenesis and reducing cell survival. These deleterious effects were associated with downregulation of vascular endothelial growth factor and endothelial NO synthetase. Conclusions Our results suggest that miR-155 dysregulation may contribute to the deleterious vascular effects of tobacco smoking.
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http://dx.doi.org/10.1161/JAHA.120.017000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955400PMC
December 2020

Open Challenges and New Perspectives in Cardiac Regenerative Medicine.

Curr Stem Cell Res Ther 2020;15(8):647-648

Mediterranea Cardiocentro, Napoli, Italy

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http://dx.doi.org/10.2174/1574888X1508201001094129DOI Listing
January 2020

The Microenvironment of Decellularized Extracellular Matrix from Heart Failure Myocardium Alters the Balance between Angiogenic and Fibrotic Signals from Stromal Primitive Cells.

Int J Mol Sci 2020 Oct 24;21(21). Epub 2020 Oct 24.

Department of Medical Surgical Sciences and Biotechnologies, Sapienza University, Corso della Repubblica 79, 04100 Latina, Italy.

Cardiac adverse remodeling is characterized by biological changes that affect the composition and architecture of the extracellular matrix (ECM). The consequently disrupted signaling can interfere with the balance between cardiogenic and pro-fibrotic phenotype of resident cardiac stromal primitive cells (CPCs). The latter are important players in cardiac homeostasis and can be exploited as therapeutic cells in regenerative medicine. Our aim was to compare the effects of human decellularized native ECM from normal (dECM-NH) or failing hearts (dECM-PH) on human CPCs. CPCs were cultured on dECM sections and characterized for gene expression, immunofluorescence, and paracrine profiles. When cultured on dECM-NH, CPCs significantly upregulated cardiac commitment markers (CX43, NKX2.5), cardioprotective cytokines (bFGF, HGF), and the angiogenesis mediator, NO. When seeded on dECM-PH, instead, CPCs upregulated pro-remodeling cytokines (IGF-2, PDGF-AA, TGF-β) and the oxidative stress molecule HO. Interestingly, culture on dECM-PH was associated with impaired paracrine support to angiogenesis, and increased expression of the vascular endothelial growth factor (VEGF)-sequestering decoy isoform of the KDR/VEGFR2 receptor. Our results suggest that resident CPCs exposed to the pathological microenvironment of remodeling ECM partially lose their paracrine angiogenic properties and release more pro-fibrotic cytokines. These observations shed novel insights on the crosstalk between ECM and stromal CPCs, suggesting also a cautious use of non-healthy decellularized myocardium for cardiac tissue engineering approaches.
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http://dx.doi.org/10.3390/ijms21217903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662394PMC
October 2020

Building an Artificial Cardiac Microenvironment: A Focus on the Extracellular Matrix.

Front Cell Dev Biol 2020 4;8:559032. Epub 2020 Sep 4.

Department of Molecular Medicine, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome, Italy.

The increased knowledge in cell signals and stem cell differentiation, together with the development of new technologies, such as 3D bioprinting, has made the generation of artificial tissues more feasible for studies and applications. In the human body, cell fate, function, and survival are determined by the microenvironment, a rich and complex network composed of extracellular matrix (ECM), different cell types, and soluble factors. They all interconnect and communicate, receiving and sending signals, modulating and responding to cues. In the cardiovascular field, the culture of stem cells and their differentiation into cardiac phenotypes is well established, although differentiated cardiomyocytes often lack the functional maturation and structural organization typical of the adult myocardium. The recreation of an artificial microenvironment as similar as possible to the native tissue, though, has been shown to partly overcome these limitations, and can be obtained through the proper combination of ECM molecules, different cell types, bioavailability of growth factors (GFs), as well as appropriate mechanical and geometrical stimuli. This review will focus on the role of the ECM in the regulation of cardiac differentiation, will provide new insights on the role of supporting cells in the generation of 3D artificial tissues, and will also present a selection of the latest approaches to recreate a cardiac microenvironment through 3D bioprinting approaches.
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http://dx.doi.org/10.3389/fcell.2020.559032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500153PMC
September 2020

Profiling the Acute Effects of Modified Risk Products: Evidence from the SUR-VAPES (Sapienza University of Rome-Vascular Assessment of Proatherosclerotic Effects of Smoking) Cluster Study.

Curr Atheroscler Rep 2020 02 7;22(2). Epub 2020 Feb 7.

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 74, 04100, Latina, Italy.

Purpose Of Review: Modified risk products (MRP) are promoted as a safer alternative to traditional combustion cigarettes (TCC) in chronic smokers. Evidence for their lower hazardous profile is building, despite several controversies. Yet, it is unclear whether individual responses to MRP differ among consumers. We hypothesized that different clusters of subjects exist in terms of acute effects of MRP.

Recent Findings: Pooling data from a total of 60 individuals, cluster analysis identified at least three clusters (labelled 1 to 3) of subjects with different electronic vaping cigarettes (EVC) effects and at least two clusters (labelled 4 to 5) of subjects with different heat-not-burn cigarettes (HNBC) effects. Specifically, oxidative stress, platelet aggregation, and endothelial dysfunction after EVC were significantly different cluster-wise (all p < 0.05), and oxidative stress and platelet aggregation after HNBC were significantly different (all p < 0.05). In particular, subjects belonging to Cluster 1 appeared to have less detrimental responses to EVC usage than subjects in Cluster 2 and 3, as shown by non-significant changes in flow-mediated dilation (FMD) and less marked increase in Nox2-derived peptide (NOX). Conversely, those assigned to Cluster 3 had the worst reaction in terms of changes in FMD, NOX, and P-selectin. Furthermore, individuals belonging to Cluster 4 responded unfavorably to both HNBC and EVC, whereas those in Cluster 5 interestingly showed less adverse results after using HNBC than EVC. Results for main analyses were consistent employing different clusters, tests, and bootstrap. Individual responses to MRP differ and smokers aiming at using EVC or HNBC as a risk reduction strategy should consider trying different MRP aiming at finding the one which is less detrimental, with subjects resembling those in Cluster 1 preferably using EVC and those resembling Cluster 5 preferably using HNBC.
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http://dx.doi.org/10.1007/s11883-020-0824-4DOI Listing
February 2020

Pharmacological restoration of autophagy reduces hypertension-related stroke occurrence.

Autophagy 2020 08 12;16(8):1468-1481. Epub 2019 Nov 12.

Department of Angio Cardio Neurology, IRCCS Neuromed, Località Camerelle , Pozzilli, Italy.

The identification of the mechanisms predisposing to stroke may improve its preventive and therapeutic strategies in patients with essential hypertension. The role of macroautophagy/autophagy in the development of hypertension-related stroke needs to be clarified. We hypothesized that a defective autophagy may favor hypertension-related spontaneous stroke by promoting mitochondrial dysfunction. We studied autophagy in the stroke-prone spontaneously hypertensive (SHRSP) rat, which represents a clinically relevant model of stroke associated with high blood pressure. We assessed autophagy, mitophagy and NAD:NADH levels in brains of SHRSP and stroke-resistant SHR fed with high salt diet. Vascular smooth muscle cells silenced for the mitochondrial complex I subunit gene (NADH:ubiquinone oxidoreductase subunit C2) and cerebral endothelial cells isolated from SHRSP were also used to assess autophagy/mitophagy and mitochondrial function in response to high salt levels. We found a reduction of autophagy in brains of high salt-fed SHRSP. Autophagy impairment was associated with NDUFC2 downregulation, mitochondrial dysfunction and NAD depletion. Restoration of NAD levels by nicotinamide administration reactivated autophagy and reduced stroke development in SHRSP. A selective reactivation of autophagy/mitophagy by Tat-Beclin 1 also reduced stroke occurrence, restored autophagy/mitophagy and improved mitochondrial function. Endothelial progenitor cells (EPCs) from subjects homozygous for the thymine allele variant at /rs11237379, which is associated with deficiency and increased stroke risk, displayed an impairment of autophagy and increased senescence in response to high salt levels. EPC senescence was rescued by Tat-Beclin 1. Pharmacological activation of autophagy may represent a novel therapeutic strategy to reduce stroke occurrence in hypertension.

Abbreviations: 10 VSMCs: aortic vascular smooth muscle cells; COX4I1/COX IV: cytochrome c oxidase subunit 4I1; ECs: endothelial cells; EPCs: endothelial progenitor cells; JD: Japanese-style diet; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NAD: nicotinamide adenine dinucleotide; NDUFC2: NADH:ubiquinone oxidoreductase subunit C2; NMN: nicotinamide mononucleotide; RD: regular diet; SHRSP: stroke-prone spontaneously hypertensive rat; SHRSR: stroke-resistant spontaneously hypertensive rat.
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http://dx.doi.org/10.1080/15548627.2019.1687215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469607PMC
August 2020

On the Road to Regeneration: "Tools" and "Routes" Towards Efficient Cardiac Cell Therapy for Ischemic Cardiomyopathy.

Curr Cardiol Rep 2019 10 31;21(11):133. Epub 2019 Oct 31.

Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy.

Purpose Of Review: Cardiac regenerative medicine is a field bridging together biotechnology and surgical science. In this review, we present the explored surgical roads to cell delivery and the known effects of each delivery method on cell therapy efficiency. We also list the more recent clinical trials, exploring the safety and efficacy of delivery routes used for cardiac cell therapy approaches.

Recent Findings: There is no consensus in defining which way is the most suitable for the delivery of the different therapeutic cell types to the damaged heart tissue. In addition, it emerged that the "delivery issue" has not been systematically addressed in each clinical trial and for each and every cell type capable of cardiac repair. Cardiac damage occurring after an ischemic insult triggers a cascade of cellular events, eventually leading to heart failure through fibrosis and maladaptive remodelling. None of the pharmacological or medical interventions approved so far can rescue or reverse this phenomenon, and cardiovascular diseases are still the leading cause of death in the western world. Therefore, for nearly 20 years, regenerative medicine approaches have focused on cell therapy as a promising road to pursue, with numerous preclinical and clinical testing of cell-based therapies being studied and developed. Nonetheless, consistent clinical results are still missing to reach consensus on the most effective strategy for ischemic cardiomyopathy, based on patient selection, diagnosis and stage of the disease, therapeutic cell type, and delivery route.
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http://dx.doi.org/10.1007/s11886-019-1226-5DOI Listing
October 2019

Automated Segmentation of Fluorescence Microscopy Images for 3D Cell Detection in human-derived Cardiospheres.

Sci Rep 2019 04 30;9(1):6644. Epub 2019 Apr 30.

Department of Electronics and Telecommunications, Politecnico di Torino, Turin, 10129, Italy.

The 'cardiosphere' is a 3D cluster of cardiac progenitor cells recapitulating a stem cell niche-like microenvironment with a potential for disease and regeneration modelling of the failing human myocardium. In this multicellular 3D context, it is extremely important to decrypt the spatial distribution of cell markers for dissecting the evolution of cellular phenotypes by direct quantification of fluorescent signals in confocal microscopy. In this study, we present a fully automated method, named CARE ('CARdiosphere Evaluation'), for the segmentation of membranes and cell nuclei in human-derived cardiospheres. The proposed method is tested on twenty 3D-stacks of cardiospheres, for a total of 1160 images. Automatic results are compared with manual annotations and two open-source software designed for fluorescence microscopy. CARE performance was excellent in cardiospheres membrane segmentation and, in cell nuclei detection, the algorithm achieved the same performance as two expert operators. To the best of our knowledge, CARE is the first fully automated algorithm for segmentation inside in vitro 3D cell spheroids, including cardiospheres. The proposed approach will provide, in the future, automated quantitative analysis of markers distribution within the cardiac niche-like environment, enabling predictive associations between cell mechanical stresses and dynamic phenotypic changes.
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http://dx.doi.org/10.1038/s41598-019-43137-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491482PMC
April 2019

Acute Effects of Heat-Not-Burn, Electronic Vaping, and Traditional Tobacco Combustion Cigarettes: The Sapienza University of Rome-Vascular Assessment of Proatherosclerotic Effects of Smoking ( SUR - VAPES ) 2 Randomized Trial.

J Am Heart Assoc 2019 03;8(6):e010455

2 IRCCS NEUROMED Pozzilli Italy.

Background Little clinical research on new-generation heat-not-burn cigarettes ( HNBC ) in comparison with electronic vaping cigarettes ( EVC ) and traditional tobacco combustion cigarettes ( TC ) has been reported. We aimed to appraise the acute effects of single use of HNBC , EVC, and TC in healthy smokers. Methods and Results This was an independent, cross-over, randomized trial in 20 TC smokers, with allocation to different cycles of HNBC , EVC , and TC . All participants used all types of products, with an intercycle washout of 1 week. End points were oxidative stress, antioxidant reserve, platelet activation, flow-mediated dilation, blood pressure, and satisfaction scores. Single use of any product led to an adverse impact on oxidative stress, antioxidant reserve, platelet function, flow-mediated dilation, and blood pressure. HNBC had less impact than EVC and TC on soluble Nox2-derived peptide (respectively, P=0.004 and 0.001), 8-iso-prostaglandin F2α- III ( P=0.004 and <0.001), and vitamin E ( P=0.018 and 0.044). HNBC and EVC were equally less impactful than TCs on flow-mediated dilation ( P=0.872 for HNBC versus EVC ), HO ( P=0.522), HO breakdown activity ( P=0.091), soluble CD 40 ligand ( P=0.849), and soluble P-selectin ( P=0.821). The effect of HNBC and, to a lesser extent EVC , on blood pressure was less evident than that of TC , whereas HNBC appeared more satisfying than EVC (all P<0.05). Conclusions Acute effects of HNBC , EVC, and TC are different on several oxidative stress, antioxidant reserve, platelet function, cardiovascular, and satisfaction dimensions, with TCs showing the most detrimental changes in clinically relevant features. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 03301129.
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http://dx.doi.org/10.1161/JAHA.118.010455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475061PMC
March 2019

Oral Plaque from Type 2 Diabetic Patients Reduces the Clonogenic Capacity of Dental Pulp-Derived Mesenchymal Stem Cells.

Stem Cells Int 2019 14;2019:1516746. Epub 2019 Jan 14.

Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, C.so della Repubblica 79, 04100 Latina, Italy.

Type 2 diabetes (T2D) is a major metabolic disease and a key epigenetic risk factor for the development of additional clinical complications. Among them, periodontitis (PD), a severe inflammatory disease ascribable to a dysregulated physiology and composition of the oral microbiota, represents one of the most relevant complications. Periodontitis can impact the structure of the tooth and likely the stem and progenitor cell pool, which actively contributes to the periodontal microenvironment and homeostasis. Modifications of the oral plaque play a key role in the etiopathogenesis of PD caused by T2D. However, to what extent the biology of the progenitor pool is affected has still to be elucidated. In this short report, we aimed to explore the biological effects of oral plaque derived from T2D patients with PD in comparison to non-diabetic patients with PD. Oral plaque samples were isolated from T2D and non-diabetic subjects with PD. Dental pulp stem cells (DPSCs), derived from the premolar tooth, were conditioned for 21 days with oral plaque samples and tested for their clonogenic ability. Cultures were also induced to differentiate towards the osteogenic lineage, and ALP and osteocalcin gene expression levels were evaluated by real-time qPCR. Results have shown that the number of clones generated by DPSCs exposed to T2D oral plaque was significantly lower compared to controls (ctl). The multivariate analysis confirmed that the decreased clonogenesis was significantly correlated only with T2D diagnosis. Moreover, the effect of T2D oral plaque was specific to DPSCs. Indicators of osteogenic differentiation were not significantly affected. This study provides a new biological insight into the effects ascribable to T2D in PD.
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http://dx.doi.org/10.1155/2019/1516746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348930PMC
January 2019

The Biological Mechanisms of Action of Cardiac Progenitor Cell Therapy.

Curr Cardiol Rep 2018 08 13;20(10):84. Epub 2018 Aug 13.

Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Corso della Repubblica 79, 04100, Latina, Italy.

Purpose Of Review: Cell therapy for cardiovascular diseases is regarded as a rapidly growing field within regenerative medicine. Different cellular populations enriched for cardiac progenitor cells (CPCs), or derivate a-cellular products, are currently under preclinical and clinical evaluation. Here, we have reviewed the described mechanisms whereby resident post-natal CPCs, isolated in different ways, act as a therapeutic product on the damaged myocardium.

Recent Findings: Several biological mechanisms of action have been described which can explain the multiple therapeutic effects of CPC treatment observed on cardiac function and remodelling. These mechanisms span from direct cardiovascular differentiation, through induction of resident progenitor proliferation, to paracrine effects on cardiac and non-cardiac cells mediated by exosomes and non-coding RNAs. All the reported mechanisms of action support an integrated view including cardiomyogenesis, cardioprotection, and anti-fibrotic effects. Moreover, future developments of CPC therapy approaches may support cell-free strategies, exploiting effective pleiotropic cell-derived products, such as exosomes.
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http://dx.doi.org/10.1007/s11886-018-1031-6DOI Listing
August 2018

Cell-Derived Exosomes for Cardiovascular Therapies: Y (Not) RNAs?

Hypertension 2018 08 4;72(2):279-280. Epub 2018 Jun 4.

From the Department of Medical Surgical Sciences and Biotechnologies, La Sapienza University of Rome, Italy (I.C., G.F.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.10684DOI Listing
August 2018

β-adrenergic receptors and cardiac progenitor cell biology: What is the real connection?

J Cell Biochem 2018 09 24;119(9):7125-7126. Epub 2018 May 24.

Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Latina, Italy.

Resident cardiac progenitor cells (CPCs) isolated from small animal models may not always be representative of their human counterparts, especially when significant differences in isolation protocols are considered. Nonetheless, multiple evidences support an important role of β-adrenergic signaling in human CPC survival and commitment, which will need appropriate consideration for future developments of human CPCs as regenerative medicine tools.
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http://dx.doi.org/10.1002/jcb.27044DOI Listing
September 2018

Predictors of oxidative stress and vascular function in an experimental study of tobacco versus electronic cigarettes: A post hoc analysis of the SUR-VAPES 1 Study.

Tob Induc Dis 2018 8;16:18. Epub 2018 May 8.

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.

Introduction: Use of a conventional cigarette (CC) or electronic cigarette (EC) leads to oxidative stress and endothelial dysfunction, but the impact of other features and their interplay with CCs and ECs have been incompletely appraised. We explored moderators of CC and EC effects on oxidative stress and endothelial dysfunction.

Methods: We have conducted an experimental study on CCs and ECs in which repeated indicators of oxidative stress (serum levels of soluble NOX2-derived peptide, nitric oxide bioavailability, 8-iso-prostaglandin F2α-III, and vitamin E) and endothelial dysfunction (flow-mediated dilation) were collected in 40 subjects (20 smokers, 20 non-smokers). Several moderating features were appraised, adjusting for smoking status and cigarette type.

Results: Absolute changes in oxidative stress and vascular features after smoking a CC or vaping an EC were significantly correlated (all p<0.05), with the notable exception of 8-iso-prostaglandin F2α-III levels (p=0.030). Inferential analysis based on generalized estimating equations highlighted that the only variable significantly associated with oxidative stress and vascular features was smoking status (all p<0.05). Specifically, we found that smokers had a less pronounced untoward oxidative and vascular response after vaping an EC in comparison to non-smokers, who had oxidative and vascular reactions to an EC that resembled more those seen after smoking a CC. Intriguingly, women taking oral contraceptives appeared to have more unfavorable changes in vitamin E (p=0.002) and FMD (p=0.008).

Conclusions: This study suggests that the comparative oxidative and vascular effects of an EC versus a CC may be influenced by smoking status, with a potential interaction in women taking oral contraceptives. These findings need further confirmation but could have important clinical and policy implications.

Abbreviations: SUR-VAPES: Sapienza University of Rome-Vascular Assessment of Proatherosclerotic Effects of Smoking.
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http://dx.doi.org/10.18332/tid/89975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659516PMC
May 2018

Cardiac Progenitor Cells: The Matrix Has You.

Stem Cells Transl Med 2018 07 24;7(7):506-510. Epub 2018 Apr 24.

Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Latina, Italy.

Components of the cardiac extracellular matrix (ECM) are synthesized by residing cells and are continuously remodeled by them. Conversely, residing cells (including primitive cells) receive constant biochemical and mechanical signals from the ECM that modulate their biology. The pathological progression of heart failure affects all residing cells, inevitably causing profound changes in ECM composition and architecture that, in turn, impact on cell phenotypes. Any regenerative medicine approach must aim at sustaining microenvironment conditions that favor cardiogenic commitment of therapeutic cells and minimize pro-fibrotic signals, while conversely boosting the capacity of therapeutic cells to counteract adverse remodeling of the ECM. In this Perspective article, we discuss multiple issues about the features of an optimal scaffold for supporting cardiac tissue engineering strategies with cardiac progenitor cells, and, conversely, about the possible antifibrotic mechanisms induced by cell therapy. Stem Cells Translational Medicine 2018;7:506-510.
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http://dx.doi.org/10.1002/sctm.18-0023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052608PMC
July 2018

Sex Differences of Human Cardiac Progenitor Cells in the Biological Response to TNF- Treatment.

Stem Cells Int 2017 17;2017:4790563. Epub 2017 Sep 17.

Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Rome, Italy.

Adult cardiac progenitor cells (CPCs), isolated as cardiosphere-derived cells (CDCs), represent promising candidates for cardiac regenerative therapy. CDCs can be expanded in vitro manyfolds without losing their differentiation potential, reaching numbers that are appropriate for clinical applications. Since mechanisms of successful CDC survival and engraftment in the damaged myocardium are still critical and unresolved issues, we aimed at deciphering possible key factors capable of bolstering CDC function. In particular, the response and the phenotype of CDCs exposed to low concentrations of the multifunctional cytokine tumor necrosis factor (TNF-), known to be capable of activating cell survival pathways, have been investigated. Furthermore, differential biological responses of CDCs from male and female donors, in terms of cell cycle progression and cell spreading, have also been assessed. The results obtained indicate that (i) the intracellular signaling activated in our experimental conditions is most likely due to the prosurvival and proliferative signaling of TNF- receptor 2 and that (ii) cells from female patients appear more responsive to TNF- treatment in terms of cell cycle progression and migration ability. In conclusion, the present report highlights the hypothesis that TNF-stimulated CDCs isolated from females may represent a promising candidate for cardiac regenerative therapy applications.
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http://dx.doi.org/10.1155/2017/4790563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623773PMC
September 2017

Getting Old through the Blood: Circulating Molecules in Aging and Senescence of Cardiovascular Regenerative Cells.

Front Cardiovasc Med 2017 6;4:62. Epub 2017 Oct 6.

Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Latina, Italy.

Global aging is a hallmark of our century. The natural multifactorial process resulting in aging involves structural and functional changes, affecting molecules, cells, and tissues. As the western population is getting older, we are witnessing an increase in the burden of cardiovascular events, some of which are known to be directly linked to cellular senescence and dysfunction. In this review, we will focus on the description of a few circulating molecules, which have been correlated to life span, aging, and cardiovascular homeostasis. We will review the current literature concerning the circulating levels and related signaling pathways of selected proteins (insulin-like growth factor 1, growth and differentiation factor-11, and PAI-1) and microRNAs of interest (miR-34a, miR-146a, miR-21), whose bloodstream levels have been associated to aging in different organisms. In particular, we will also discuss their potential role in the biology and senescence of cardiovascular regenerative cell types, such as endothelial progenitor cells, mesenchymal stromal cells, and cardiac progenitor cells.
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http://dx.doi.org/10.3389/fcvm.2017.00062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635266PMC
October 2017

EMT/MET at the Crossroad of Stemness, Regeneration and Oncogenesis: The Ying-Yang Equilibrium Recapitulated in Cell Spheroids.

Cancers (Basel) 2017 Jul 29;9(8). Epub 2017 Jul 29.

Department of Pediatrics and Infant Neuropsychiatry, "Umberto I" Hospital, "La Sapienza" University of Rome, 00195 Roma, Italy.

The epithelial-to-mesenchymal transition (EMT) is an essential trans-differentiation process, which plays a critical role in embryonic development, wound healing, tissue regeneration, organ fibrosis, and cancer progression. It is the fundamental mechanism by which epithelial cells lose many of their characteristics while acquiring features typical of mesenchymal cells, such as migratory capacity and invasiveness. Depending on the contest, EMT is complemented and balanced by the reverse process, the mesenchymal-to-epithelial transition (MET). In the saving economy of the living organisms, the same (Ying-Yang) tool is integrated as a physiological strategy in embryonic development, as well as in the course of reparative or disease processes, prominently fibrosis, tumor invasion and metastasis. These mechanisms and their related signaling (e.g., TGF-β and BMPs) have been effectively studied in vitro by tissue-derived cell spheroids models. These three-dimensional (3D) cell culture systems, whose phenotype has been shown to be strongly dependent on TGF-β-regulated EMT/MET processes, present the advantage of recapitulating in vitro the hypoxic in vivo micro-environment of tissue stem cell niches and their formation. These spheroids, therefore, nicely reproduce the finely regulated Ying-Yang equilibrium, which, together with other mechanisms, can be determinant in cell fate decisions in many pathophysiological scenarios, such as differentiation, fibrosis, regeneration, and oncogenesis. In this review, current progress in the knowledge of signaling pathways affecting EMT/MET and stemness regulation will be outlined by comparing data obtained from cellular spheroids systems, as ex vivo niches of stem cells derived from normal and tumoral tissues. The mechanistic correspondence in vivo and the possible pharmacological perspective will be also explored, focusing especially on the TGF-β-related networks, as well as others, such as SNAI1, PTEN, and EGR1. This latter, in particular, for its ability to convey multiple types of stimuli into relevant changes of the cell transcriptional program, can be regarded as a heterogeneous "stress-sensor" for EMT-related inducers (growth factor, hypoxia, mechano-stress), and thus as a therapeutic target.
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http://dx.doi.org/10.3390/cancers9080098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575601PMC
July 2017

A Review of the Molecular Mechanisms Underlying the Development and Progression of Cardiac Remodeling.

Oxid Med Cell Longev 2017 2;2017:3920195. Epub 2017 Jul 2.

Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Latina, Italy.

Pathological molecular mechanisms involved in myocardial remodeling contribute to alter the existing structure of the heart, leading to cardiac dysfunction. Among the complex signaling network that characterizes myocardial remodeling, the distinct processes are myocyte loss, cardiac hypertrophy, alteration of extracellular matrix homeostasis, fibrosis, defective autophagy, metabolic abnormalities, and mitochondrial dysfunction. Several pathophysiological stimuli, such as pressure and volume overload, trigger the remodeling cascade, a process that initially confers protection to the heart as a compensatory mechanism. Yet chronic inflammation after myocardial infarction also leads to cardiac remodeling that, when prolonged, leads to heart failure progression. Here, we review the molecular pathways involved in cardiac remodeling, with particular emphasis on those associated with myocardial infarction. A better understanding of cell signaling involved in cardiac remodeling may support the development of new therapeutic strategies towards the treatment of heart failure and reduction of cardiac complications. We will also discuss data derived from gene therapy approaches for modulating key mediators of cardiac remodeling.
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http://dx.doi.org/10.1155/2017/3920195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511646PMC
April 2018

Normal versus Pathological Cardiac Fibroblast-Derived Extracellular Matrix Differentially Modulates Cardiosphere-Derived Cell Paracrine Properties and Commitment.

Stem Cells Int 2017 27;2017:7396462. Epub 2017 Jun 27.

Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Rome, Italy.

Human resident cardiac progenitor cells (CPCs) isolated as cardiosphere-derived cells (CDCs) are under clinical evaluation as a therapeutic product for cardiac regenerative medicine. Unfortunately, limited engraftment and differentiation potential of transplanted cells significantly hamper therapeutic success. Moreover, maladaptive remodelling of the extracellular matrix (ECM) during heart failure progression provides impaired biological and mechanical signals to cardiac cells, including CPCs. In this study, we aimed at investigating the differential effect on the phenotype of human CDCs of cardiac fibroblast-derived ECM substrates from healthy or diseased hearts, named, respectively, normal or pathological cardiogel (CG-N/P). After 7 days of culture, results show increased levels of cardiogenic gene expression (NKX2.5, CX43) on both decellularized cardiogels compared to control, while the proportion and staining patterns of GATA4, OCT4, NKX2.5, ACTA1, VIM, and CD90-positive CPCs were not affected, as assessed by immunofluorescence microscopy and flow cytometry analyses. Nonetheless, CDCs cultured on CG-N secreted significantly higher levels of osteopontin, FGF6, FGF7, NT-3, IGFBP4, and TIMP-2 compared to those cultured on CG-P, suggesting overall a reduced trophic and antiremodelling paracrine profile of CDCs when in contact with ECM from pathological cardiac fibroblasts. These results provide novel insights into the bidirectional interplay between cardiac ECM and CPCs, potentially affecting CPC biology and regenerative potential.
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http://dx.doi.org/10.1155/2017/7396462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504962PMC
June 2017

Histone acetylation favours the cardiovascular commitment of adipose tissue-derived stromal cells.

Int J Cardiol 2017 Sep 2;243:421-423. Epub 2017 Jun 2.

Department of Medical-Surgical Sciences and Biotechnologies, "Sapienza" University of Rome, C.so della Repubblica 79, 04100 Latina, Italy; Department of AngioCardioNeurology, IRCCS NeuroMed, 86077 Pozzilli, IS, Italy.

Background: Although adipose stromal cells (ASCs) retain the ability to transdifferentiate at low rate towards the cardiac lineage, the potential mechanisms underlying such process have still to be elucidated.

Methods: Since chromatin state modifications are involved in several processes regulating the cellular cell fate commitment, we aimed at evaluating the role of histone protein acetylation in the cardiovascular-like transdifferentiation of ASCs.

Results: We found a clear increase of histone 3 acetylation status paralleled by a significant upregulation of cardiac TnI gene expression, in ASCs treated with the conditioned medium of primary cardiomyocyte cell cultures for 72h. This result suggests that histone acetylation contributes to the transdifferentiation of ASCs towards the cardiac lineage. In order to directly test this hypothesis, ASCs cultured with regular medium were treated with SAHA, a pan histone deacetylase inhibitor. We found that SAHA enhanced the cardiac permissive state of ASCs, increasing both mRNA and protein expression of cardiovascular genes, particularly cTnI. This suggests that histone acetylation induction is sufficient to promote cardiovascular transdifferentiation.

Conclusions: The control of ASC fate by epigenetic regulators might be an interesting tool to boost both cardiac commitment and regenerative capacities of ASCs.
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http://dx.doi.org/10.1016/j.ijcard.2017.05.112DOI Listing
September 2017

The Impact of Environmental Factors in Influencing Epigenetics Related to Oxidative States in the Cardiovascular System.

Oxid Med Cell Longev 2017 14;2017:2712751. Epub 2017 May 14.

Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.

Oxidative states exert a significant influence on a wide range of biological and molecular processes and functions. When their balance is shifted towards enhanced amounts of free radicals, pathological phenomena can occur, as the generation of reactive oxygen species (ROS) in tissue microenvironment or in the systemic circulation can be detrimental. Epidemic chronic diseases of western societies, such as cardiovascular disease, obesity, and diabetes correlate with the imbalance of redox homeostasis. Current advances in our understanding of epigenetics have revealed a parallel scenario showing the influence of oxidative stress as a major regulator of epigenetic gene regulation via modification of DNA methylation, histones, and microRNAs. This has provided both the biological link and a potential molecular explanation between oxidative stress and cardiovascular/metabolic phenomena. Accordingly, in this review, we will provide current insights on the physiological and pathological impact of changes in oxidative states on cardiovascular disorders, by specifically focusing on the influence of epigenetic regulation. A special emphasis will highlight the effect on epigenetic regulation of human's current life habits, external and environmental factors, including food intake, tobacco, air pollution, and antioxidant-based approaches. Additionally, the strategy to quantify oxidative states in humans in order to determine which biological marker could best match a subject's profile will be discussed.
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http://dx.doi.org/10.1155/2017/2712751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457758PMC
March 2018

An overview of the inflammatory signalling mechanisms in the myocardium underlying the development of diabetic cardiomyopathy.

Cardiovasc Res 2017 Mar;113(4):378-388

Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, 04100 Latina (LT), Italy.

Heart failure is a highly morbid and mortal clinical condition that represents the last stage of most cardiovascular disorders. Diabetes is strongly associated with an increased incidence of heart failure and directly promotes cardiac hypertrophy, fibrosis, and apoptosis. These changes, in turn, contribute to the development of ventricular dysfunction. The clinical condition associated with the spectrum of cardiac abnormalities induced by diabetes is termed diabetic cardiomyopathy. Myocardial inflammation has recently emerged as a pathophysiological process contributing to cardiac hypertrophy, fibrosis, and dysfunction in cardiac diseases. Myocardial inflammation is also implicated in the development of diabetic cardiomyopathy. Several molecular mechanisms link diabetes to myocardial inflammation. The NF-κB signalling pathway and the renin-angiotensin-aldosterone system are strongly activated in the diabetic heart, thereby promoting myocardial inflammation. Advanced glycation end-products and damage-associated molecular pattern molecules also represent strong triggers for inflammation. The mediators resulting from this inflammatory process modulate specific intracellular signalling mechanisms in cardiac cells that promote the development of diabetic cardiomyopathy. This review article will provide an overview of the signalling molecular mechanisms linking diabetic cardiomyopathy to myocardial inflammation.
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http://dx.doi.org/10.1093/cvr/cvx011DOI Listing
March 2017

Human Lung Spheroids as In Vitro Niches of Lung Progenitor Cells with Distinctive Paracrine and Plasticity Properties.

Stem Cells Transl Med 2017 03 22;6(3):767-777. Epub 2016 Sep 22.

Department of Medical-Surgical Sciences and Biotechnology, "Sapienza" University of Rome, Rome, Italy.

Basic and translational research on lung biology has discovered multiple progenitor cell types, specialized or facultative, responsible for turnover, renewal, and repair. Isolation of populations of resident lung progenitor cells (LPCs) has been described by multiple protocols, and some have been successfully applied to healthy human lung tissue. We aimed at understanding how different cell culture conditions may affect, in vitro, the phenotype of LPCs to create an ideal niche-like microenvironment. The influence of different substrates (i.e., fibronectin, gelatin, laminin) and the impact of a three-dimensional/two-dimensional (3D/2D) culture switch on the biology of LPCs isolated as lung spheroids (LSs) from normal adult human lung biopsy specimens were investigated. We applied a spheroid culture system as the selective/inductive step for progenitor cell culture, as described in many biological systems. The data showed a niche-like proepithelial microenvironment inside the LS, highly sensitive to the 3D culture system and significantly affecting the phenotype of adult LPCs more than culture substrate. LSs favor epithelial phenotypes and LPC maintenance and contain cells more responsive to specific commitment stimuli than 2D monolayer cultures, while secreting a distinctive set of paracrine factors. We have shown for the first time, to our knowledge, how culture as 3D LSs can affect LPC epithelial phenotype and produce strong paracrine signals with a distinctive secretomic profile compared with 2D monolayer conditions. These findings suggest novel approaches to maintain ex vivo LPCs for basic and translational studies. Stem Cells Translational Medicine 2017;6:767-777.
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http://dx.doi.org/10.5966/sctm.2015-0374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442776PMC
March 2017

Stem Cell Spheroids and Ex Vivo Niche Modeling: Rationalization and Scaling-Up.

J Cardiovasc Transl Res 2017 Apr 13;10(2):150-166. Epub 2017 Mar 13.

Department of Pediatrics and Infant Neuropsychiatry, "Umberto I" Hospital, "La Sapienza" University, Viale Regina Elena 324, 00161, Rome, Italy.

Improved protocols/devices for in vitro culture of 3D cell spheroids may provide essential cues for proper growth and differentiation of stem/progenitor cells (S/PCs) in their niche, allowing preservation of specific features, such as multi-lineage potential and paracrine activity. Several platforms have been employed to replicate these conditions and to generate S/PC spheroids for therapeutic applications. However, they incompletely reproduce the niche environment, with partial loss of its highly regulated network, with additional hurdles in the field of cardiac biology, due to debated resident S/PCs therapeutic potential and clinical translation. In this contribution, the essential niche conditions (metabolic, geometric, mechanical) that allow S/PCs maintenance/commitment will be discussed. In particular, we will focus on both existing bioreactor-based platforms for the culture of S/PC as spheroids, and on possible criteria for the scaling-up of niche-like spheroids, which could be envisaged as promising tools for personalized cardiac regenerative medicine, as well as for high-throughput drug screening.
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http://dx.doi.org/10.1007/s12265-017-9741-5DOI Listing
April 2017

Beta2-adrenergic signaling affects the phenotype of human cardiac progenitor cells through EMT modulation.

Pharmacol Res 2018 01 15;127:41-48. Epub 2017 Jan 15.

Department of Medical Surgical Sciences and Biotechnology, "La Sapienza" University of Rome, Italy. Electronic address:

Human cardiac progenitor cells (CPCs) offer great promises to cardiac cell therapy for heart failure. Many in vivo studies have shown their therapeutic benefits, paving the way for clinical translation. The 3D model of cardiospheres (CSs) represents a unique niche-like in vitro microenvironment, which includes CPCs and supporting cells. CSs have been shown to form through a process mediated by epithelial-to-mesenchymal transition (EMT). β2-Adrenergic signaling significantly affects stem/progenitor cells activation and mobilization in multiple tissues, and crosstalk between β2-adrenergic signaling and EMT processes has been reported. In the present study, we aimed at investigating the biological response of CSs to β2-adrenergic stimuli, focusing on EMT modulation in the 3D culture system of CSs. We treated human CSs and CS-derived cells (CDCs) with the β2-blocker butoxamine (BUT), using either untreated or β2 agonist (clenbuterol) treated CDCs as control. BUT-treated CS-forming cells displayed increased migration capacity and a significant increase in their CS-forming ability, consistently associated with increased expression of EMT-related genes, such as Snai1. Moreover, long-term BUT-treated CDCs contained a lower percentage of CD90+ cells, and this feature has been previously correlated with higher cardiogenic and therapeutic potential of the CDCs population. In addition, long-term BUT-treated CDCs had an increased ratio of collagen-III/collagen-I gene expression levels, and showed decreased release of inflammatory cytokines, overall supporting a less fibrosis-prone phenotype. In conclusion, β2 adrenergic receptor block positively affected the stemness vs commitment balance within CSs through the modulation of type1-EMT (so called "developmental"). These results further highlight type-1 EMT to be a key process affecting the features of resident cardiac progenitor cells, and mediating their response to the microenvironment.
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http://dx.doi.org/10.1016/j.phrs.2017.01.016DOI Listing
January 2018

Β-blockers treatment of cardiac surgery patients enhances isolation and improves phenotype of cardiosphere-derived cells.

Sci Rep 2016 11 14;6:36774. Epub 2016 Nov 14.

Department of Medical Surgical Sciences and Biotechnology, "La Sapienza" University of Rome, Italy.

Β-blockers (BB) are a primary treatment for chronic heart disease (CHD), resulting in prognostic and symptomatic benefits. Cardiac cell therapy represents a promising regenerative treatment and, for autologous cell therapy, the patients clinical history may correlate with the biology of resident progenitors and the quality of the final cell product. This study aimed at uncovering correlations between clinical records of biopsy-donor CHD patients undergoing cardiac surgery and the corresponding yield and phenotype of cardiospheres (CSs) and CS-derived cells (CDCs), which are a clinically relevant population for cell therapy, containing progenitors. We describe a statistically significant association between BB therapy and improved CSs yield and CDCs phenotype. We show that BB-CDCs have a reduced fibrotic-like CD90 + subpopulation, with reduced expression of collagen-I and increased expression of cardiac genes, compared to CDCs from non-BB donors. Moreover BB-CDCs had a distinctive microRNA expression profile, consistent with reduced fibrotic features (miR-21, miR-29a/b/c downregulation), and enhanced regenerative potential (miR-1, miR-133, miR-101 upregulation) compared to non-BB. In vitro adrenergic pharmacological treatments confirmed cytoprotective and anti-fibrotic effects of β1-blocker on CDCs. This study shows anti-fibrotic and pro-commitment effects of BB treatment on endogenous cardiac reparative cells, and suggests adjuvant roles of β-blockers in cell therapy applications.
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http://dx.doi.org/10.1038/srep36774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107949PMC
November 2016

The adipose tissue of origin influences the biological potential of human adipose stromal cells isolated from mediastinal and subcutaneous fat depots.

Stem Cell Res 2016 09 30;17(2):342-351. Epub 2016 Jul 30.

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, C.so della Repubblica 79, 04100 Latina, Italy. Electronic address:

Indirect evidence suggests that adipose tissue-derived stromal cells (ASCs) possess different physiological and biological variations related to the anatomical localization of the adipose depots. Accordingly, to investigate the influence of the tissue origin on the intrinsic properties of ASCs and to assess their response to specific stimuli, we compared the biological, functional and ultrastructural properties of two ASC pools derived from mediastinal and subcutaneous depots (thoracic compartment) by means of supplements such as platelet lysate (PL) and FBS. Subcutaneous ASCs exhibited higher proliferative and clonogenic abilities than mediastinal counterpart, as well as increased secreted levels of IL-6 combined with lower amount of VEGF-C. In contrast, mediastinal ASCs displayed enhanced pro-angiogenic and adipogenic differentiation properties, increased cell diameter and early autophagic processes, highlighted by electron microscopy. Our results further support the hypothesis that the origin of adipose tissue significantly defines the biological properties of ASCs, and that a homogeneric function for all ASCs cannot be assumed.
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http://dx.doi.org/10.1016/j.scr.2016.07.010DOI Listing
September 2016
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