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Barczyk M.,Stem Cell Research Center | Barczyk M.,Avail Biomedical Research Institute | Schmidt M.,Discovery and Translational Research Center | Schmidt M.,Avail Biomedical Research Institute | Mattoli S.,Avail Biomedical Research Institute
Stem Cell Reviews and Reports | Year: 2015

Idiopathic pulmonary fibrosis is a progressive fibrosing disorder for which there is no cure and no pharmacological treatment capable of increasing in a meaningful way the survival rate. Lung transplantation remains the only possible treatment for patients with advanced disease, although the increase in 5-year survival is only 45%. Some preclinical studies have generated promising results about the therapeutic potential of exogenous stem cells. However, two initial clinical trials involving the endobronchial or systemic delivery of autologous adipose tissue-derived or unrelated-donor, placenta-derived mesenchymal stem cells have not convincingly demonstrated that these treatments are acceptably safe. The results of other ongoing clinical trials may help to identify the best source and delivery route of mesenchymal stem cells and to estimate the risk of unwanted effects related to the mesenchymal nature of the transplanted cells. Considering that most of the therapeutic potential of these cells has been ascribed to paracrine signaling, the use of mesenchymal stem cell-derived secretome as an alternative to the transplantation of single cell suspension may circumventmany regulatory and clinical problems. Technical and safety concerns still limit the possibility of clinical applications of other promising interventions that are based on the use of human amnion stem cells, embryonic stem cells or induced pluripotent stem cells to replace or regenerate the dysfunctional alveolar epithelium. We summarize the current status of the field and identify major challenges and opportunities for the possible future integration of stem cell-based treatments into the currently recommended clinical management strategy for idiopathic pulmonary fibrosis. © Springer Science+Business Media New York 2015.


Bellini A.,Avail Biomedical Research Institute | Marini M.A.,Multispecialty Outpatient Clinic and Diagnostic Center | Bianchetti L.,Avail Biomedical Research Institute | Barczyk M.,Avail Biomedical Research Institute | And 2 more authors.
Mucosal Immunology | Year: 2012

Fibrocytes contribute to the fibrotic changes most frequently observed in forms of asthma where inflammation is driven by T helper type 2 (Th2) cells. The mechanisms that regulate the profibrotic function of asthmatic fibrocytes are largely unknown. We isolated circulating fibrocytes from patients with allergen-exacerbated asthma, who showed the presence of fibrocytes, together with elevated concentrations of interleukin (IL)-4 and IL-13 and slightly increased concentrations of the Th17 cell-derived IL-17A, in induced sputum. Fibrocytes stimulated with IL-4 and IL-13 produced high levels of collagenous and non-collagenous matrix components and low levels of proinflammatory cytokines. Conversely, fibrocytes stimulated with IL-17A proliferated and released proinflammatory factors that may promote neutrophil recruitment and airway hyperresponsiveness. IL-17A also indirectly increased α-smooth muscle actin but not collagen expression in fibrocytes. Thus, fibrocytes may proliferate and express a predominant profibrotic or proinflammatory phenotype in asthmatic airways depending on the local concentrations of Th2- and Th17-derived cytokines. 2012 Society for Mucosal Immunology.


Bianchetti L.,Avail Biomedical Research Institute | Bianchetti L.,Italian ABR Operative Unit | Marini M.A.,Multispecialty Outpatient Clinic and Diagnostic Center | Isgro M.,Avail Biomedical Research Institute | And 4 more authors.
Biochemical and Biophysical Research Communications | Year: 2012

The release of IL-33 increases in the bronchial mucosa of asthmatic patients in relation to disease severity and several studies have demonstrated that IL-33 may enhance airway inflammation in asthma. This study tested the hypothesis that IL-33 may also contribute to the development of irreversible structural changes in asthma by favoring the airway recruitment and profibrotic function of circulating fibrocytes during episodes of allergen-induced asthma exacerbation. The circulating fibrocytes from patients with allergen-exacerbated asthma (PwAA) showed increased expression of the specific IL-33 receptor component ST2L in comparison with the cells from non-asthmatic individuals (NAI). Recombinant IL-33 induced the migration of circulating fibrocytes from PwAA at clinically relevant concentrations and stimulated their proliferation in a concentration-dependent manner between 0.1 and 10. ng/ml, without affecting the constitutive release of type I collagen. The recombinant protein did not induce similar responses in circulating fibrocytes from NAI. This study uncovers an important mechanism through which fibrocytes may accumulate in the airways of allergic asthmatics when their disease is not adequately controlled by current treatment and provides novel information on the function of IL-33 in asthma. © 2012 Elsevier Inc.


Isgro M.,Avail Biomedical Research Institute | Isgro M.,Italian ABR Operative Unit | Bianchetti L.,Avail Biomedical Research Institute | Bianchetti L.,Italian ABR Operative Unit | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2013

Allergen exposure and rhinovirus infections that propagate from the upper to the lower airways are the most frequent causes of asthma exacerbation. In patients at increased risk of disease exacerbations, chronic airway inflammation is associated with the airway recruitment of circulating fibrocytes, bone marrow-derived CD34+CD45RO+CD11b+CD13+HLA-DR+ progenitors that have antigen-presenting function and fibroblast-like properties. This study demonstrates that allergen-pulsed circulating fibrocytes from patients with allergic asthma are potent inducer of the predominant release of the T helper type (Th)2 cytokines IL-4 and IL-5 from autologous naïve and memory CD4+ T cells. This study also provides evidence that circulating fibrocytes from allergic asthmatics are susceptible to rhinovirus infection. Infected cells release high amounts of pro-inflammatory cytokines with minimal production of IFN-α/β. Moreover, allergen-pulsed fibrocytes support prolonged rhinovirus replication and release larger quantities of pro-inflammatory cytokines upon rhinovirus infection than unpulsed fibrocytes. Thus, fibrocytes may amplify allergen-induced, Th2 cell-driven inflammatory responses and promote further inflammation by functioning as a reservoir for rhinovirus replication in asthmatic airways. Through these mechanisms, fibrocytes may play an important role in the provocation of disease exacerbations. © 2013 Elsevier Inc.


Isgro M.,Avail Biomedical Research Institute | Isgro M.,ABR Operative Unit | Bianchetti L.,Avail Biomedical Research Institute | Marini M.A.,Multispecialty Outpatient Clinic and Diagnostic Center | And 3 more authors.
Mucosal Immunology | Year: 2013

The C-C motif chemokine ligand 5 (CCL5), CCL11, and CCL24 are involved in the pathogenesis of asthma, and their function is mainly associated with the airway recruitment of eosinophils. This study tested their ability to induce the migration of circulating fibrocytes, which may contribute to the development of irreversible airflow obstruction in severe asthma. The sputum fluid phase (SFP) from patients with severe/treatment-refractory asthma (PwSA) contained elevated concentrations of CCL5, CCL11, and CCL24 in comparison with the SFP from patients with non-severe/treatment-responsive asthma (PwNSA). The circulating fibrocytes from PwSA expressed the receptors for these chemokines at increased levels and migrated in response to recombinant CCL5, CCL11, and CCL24. The SFP from PwSA induced the migration of autologous fibrocytes, and its activity was significantly attenuated by neutralization of endogenous CCL5, CCL11, and CCL24. These findings suggest that CCL5, CCL11, and CCL24 may contribute to the airway recruitment of fibrocytes in severe asthma. © 2013 Society for Mucosal Immunology.


Bianchetti L.,Avail Biomedical Research Institute | Barczyk M.,Avail Biomedical Research Institute | Cardoso J.,Avail Biomedical Research Institute | Schmidt M.,Avail Biomedical Research Institute | And 2 more authors.
Journal of Cellular and Molecular Medicine | Year: 2012

The fibrocytes are thought to serve as a source of newly deposited collagens I and III during reparative processes and in certain fibrotic disorders, but their matrix remodelling properties are incompletely understood. We evaluated their ability to produce several extracellular matrix (ECM) components, in comparison with fibroblasts, and to participate in collagen turnover. The collagen gene expression profile of fibrocytes differed from that of fibroblasts because fibrocytes constitutively expressed relatively high levels of the mRNA encoding collagen VI and significantly lower levels of the mRNA encoding collagens I, III and V. The proteoglycan (PG) gene expression profile was also different in fibrocytes and fibroblasts because fibrocytes constitutively expressed the mRNA encoding perlecan and versican at relatively high levels and the mRNA encoding biglycan and decorin at low and very low levels, respectively. Moreover, fibrocytes expressed the mRNA for hyaluronan synthase 2 at higher level than fibroblasts. Significant differences between the two cell populations were also demonstrated by metabolic labelling and analysis of the secreted collagenous proteins, PGs and hyaluronan. Fibrocytes constitutively expressed the scavenger receptors CD163 and CD204 as well as the mannose receptors CD206 and Endo180, and internalized and degraded collagen fragments through an Endo180-mediated mechanism. The results of this study demonstrate that human fibrocytes exhibit ECM remodelling properties previously unexplored, including the ability to participate in collagen turnover. The observed differences in collagen and PG expression profile between fibrocytes and fibroblasts suggest that fibrocytes may predominantly have a matrix-stabilizing function. © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.


Mattoli S.,Avail Biomedical Research Institute
Journal of Zhejiang University: Science B | Year: 2015

Bloodborne fibrocytes are cells mobilized from the bone marrow, which express surface antigens commonly ascribed to hematopoietic progenitors and have phenotypic and functional characteristics similar to those of immature mesenchymal cells. They exhibit predominant proinflammatory or profibrotic activities at tissue sites, depending on the host’s response to environmental insults and on the characteristics of the cell infiltrate and cytokine milieu. In patients with allergic asthma, fibrocytes egress from the bone marrow and are recruited into the airways after every allergen exposure and during viral infections. Recruited fibrocytes amplify the inflammatory responses driven by T helper type 2 lymphokines and favor viral replication and further inflammation on respiratory virus infections. Persistently elevated blood fibrocyte counts and persisting airway fibrocytosis are present in patients with chronically undertreated or corticosteroid-insensitive asthma, and are linked to an enhanced risk of adverse outcomes because of the major involvement of fibrocytes in the development of structural abnormalities that lead to chronic airflow obstruction in these patients. Consequently, blood fibrocyte count is an emerging biomarker of asthma control and disease progression and its clinical applicability as a new outcome measure deserves further evaluation in large clinical trials. © 2015, Zhejiang University and Springer-Verlag Berlin Heidelberg.


Schmidt M.,Avail Biomedical Research Institute | Mattoli S.,Avail Biomedical Research Institute
Methods in Molecular Biology | Year: 2013

Airway remodeling is a term used to collectively indicate bronchial structural changes that may lead to irreversible airflow obstruction and progressive decline in lung function in asthmatic patients. Bronchial myofibroblasts contribute to airway remodeling by producing collagenous proteins in the subepithelial zone and by increasing the density of contractile cells in the bronchial wall. A substantial proportion of bronchial myofibroblasts in asthma differentiate from circulating mesenchymal progenitor cells known as fibrocytes. Here, we describe a mouse model of allergic asthma for evaluating the functional role of fibrocytes and myofibroblasts in this disease and the inhibitory effects of novel therapeutic candidates. © 2013 Springer Science+Business Media, LLC.


Mattoli S.,Avail Biomedical Research Institute
Clinical and Experimental Allergy | Year: 2015

Bloodborne fibrocytes are bone marrow-derived cells that participate in immune responses and exhibit pro-inflammatory and matrix remodelling properties. In patients with asthma receiving an adequate treatment, the blood fibrocyte count is very low and comparable to that obtained in healthy individuals. In these patients, a transient increase in fibrocyte numbers in the peripheral blood and in the airways occurs in concomitance with increased bronchial inflammation and reflects disease worsening and the need for more intensive treatment. Persistently elevated numbers of fibrocytes in the peripheral blood and in the bronchial mucosa are observed in chronically undertreated or corticosteroid-resistant asthma and are associated with persistent airway inflammation and ongoing remodelling of the bronchial wall. The asthmatic bronchial epithelium is the main source of fibrocyte chemoattractants in asthma and contributes with T helper type 2 lymphocytes and eosinophils to promote the proliferation and pro-remodelling function of recruited fibrocytes. The presence of elevated numbers of fibrocytes in the bronchial mucosa of allergic patients with undertreated or treatment-resistant asthma may also increase the risk of acute exacerbations because these cells can amplify T helper type 2 lymphocyte-driven inflammation on every exposure to the clinically relevant allergen and can promote further inflammation on rhinovirus infections by allowing viral replication and releasing additional pro-inflammatory factors. Improved methods for the isolation and functional analysis of pure populations of viable circulating fibrocytes have allowed a better understanding of the effector role of these cells. A reliable and clinically applicable assay has been developed to measure blood fibrocyte counts as outcome measure in future clinical trials. New therapeutic agents are needed to block both persistent inflammation and fibrocytosis in corticosteroid-resistant asthma. © 2015 John Wiley & Sons Ltd.


Bellini A.,Avail Biomedical Research Institute | Schmidt M.,Avail Biomedical Research Institute | Mattoli S.,Avail Biomedical Research Institute
Journal of Epithelial Biology and Pharmacology | Year: 2013

The histopathologic features of asthma include chronic airway inflammation, increased density of fibroblasts and myofibroblasts in the lamina propria and presence of structural abnormalities of the bronchial wall collectively referred to with the term “airway remodeling”. The newly emerged population of fibroblasts and myofibroblasts contributes to airway remodeling by producing excessive amounts of collagenous and non-collagenous extracellular matrix components in the subepithelial zone and by expanding the mass of contractile cells in the bronchial wall. A substantial proportion of these mesenchymal cells in asthma exhibit the phenotypic and functional characteristic of fibrocytes, which represent a unique population of bone marrow-derived mesenchymal progenitors recruited to tissue sites from the circulation in response to injury or in chronic inflammatory conditions. Recent studies have demonstrated that the asthmatic bronchial epithelium is a major source of fibrocyte chemoattractants and growth factors. This review will focus on the novel observations suggesting that asthmatic epithelial cells may play a key role in the development and progression of airway remodeling by promoting the recruitment and local differentiation of fibrocytes. © 2013, (publisher). All rights reserverd.

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