Stefania Cerri, Paolo Spagnolo, Fabrizio Luppi, Luca Richeldi Meeting DAI di Oncologia, Ematologia e Patologie dellApparato Respiratorio Gaiato, 16 luglio

Slide 1 Stefania Cerri, Paolo Spagnolo, Fabrizio Luppi, Luca Richeldi Meeting DAI di Oncologia, Ematologia e Patologie dellApparato Respiratorio Gaiato, 16 luglio 2011 Fibrociti e cellule mesenchimali staminali nella fibrosi polmonare idiopatica Bando Ricerca Finalizzata 2009 – Ministero della Salute Progetto Giovani Ricercatori Slide 2 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 Fibrocytes Firstly described in 1994 1 Circulating, bone marrow-derived cells with the ability to adopt a mesenchymal phenotype Express a combination of hematopoietic and mesenchymal markers In normal individuals, approx 05% of circulating leukocytes 1 Bucala R, et al Molecular Medicine, 1994; 1(1):71-81 ControlCollagen I Slide 3 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 Fibrocytes markers They are known to be positive for both CD45 and Collagen I or pro-Collagen I They may express CD34 (stem cell marker) According to some authors, they also share monocyte markers (such CD14 and CD11) Chemokines receptors (such as CXCR4) Lack of expression of CD3, CD4, CD8, CD19 and CD25 They seem to be able to present antigens Slide 4 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 Fibrocytes markers Bellini A, Mattioli S, Laboratory Investigation 2007; 87:858-70 Slide 5 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 Fibrocytes in health and disease Fibrocytes have been described in several diseases in which fibrosis occurs – Asthma – Skin scars and keloids – Scleroderma – Liver fibrosis – Cardiac disease – Renal fibrosis Circulating fibrocytes may be increased in normal aging Herzog EL, Bucala R, Experimental Hematology 2010; 38:548-56 Slide 6 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 ATS/ERS/JRS/ALAT IPF GUIDELINES 2011 IDIOPATHIC PULMONARY FIBROSIS (IPF) Specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring in adults and limited to the lungs Slide 7 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 Slide 8 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 Pathogenesis of IPF Abnormal wound healing model Selman M, Ann Intern Med 2001; 134:136 Slide 9 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 Slide 10 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 Circulating fibrocytes in human fibrotic interstitial lung disease UIP: usual interstitial pneumonia; NSIP: non-specific interstitial pneumonia Mehrad et al Biochem Biophys Res Commun 2007; 353:104-8 Slide 11 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 Circulating fibrocytes and IPF prognosis Moeller et al Am J Respir Crit Care Med 2009; 179:588-94 Fibrocytes defined as CD45+ and Coll-1+ cells among live PBMC Slide 12 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 Circulating fibrocytes and IPF prognosis Moeller et al Am J Respir Crit Care Med 2009; 179:588-94 Fibrocytes defined as CD45+ and Coll-1+ cells among live PBMC Slide 13 AGE MATTERS Ageing mice develop more fibrosis in response to Bleomycin, have more fibrocytes Xu J et al J Gerontol A Biol Sci Med Sci 2009 MSCs of ageing mice have decreased ability to differentiate Slide 14 Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects Saline BleomycinBleomycin + BM-MSC Ortiz LA et al PNAS 2003; 100(14):8407-11 Slide 15 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 MESENCHYMAL PROGENITOR CELLS AS BIOMARKERS IN IDIOPATHIC PULMONARY FIBROSIS: A PROSPECTIVE STUDY IL PROGETTO GR-2009-1607498 Slide 16 Project aims Aim 1 Measurement and characterization of circulating fibrocytes – Longitudinal measurement of circulating fibrocytes in IPF patients and comparison with clinical outcomes – Characterization of expression markers related to lung homing and differentiation – Assessment of cytokine levels in the serum of IPF patients – Evaluation of the effects of cytokine stimulation on in vitro proliferation, differentiation and migration ability of fibrocytes isolated from IPF patients Slide 17 Project aims Aim 2 Measurement and characterization of MSC – Characterization of bone-marrow derived MSC from IPF patients (numbers and expression markers) – Correlation between MCS and fibrocytes numbers – In vitro assessment of differentiation potential of MSC derived from IPF patients Slide 18 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 Study design Total duration: 3 years Patients with a diagnosis of IPF according to ATS/ERS/JRS Guidelines 2011 Prospective enrollment of both prevalent and incident cases Collection of blood samples for fibrocytes and cytokine measurement at the enrollment and then every 6 months during the follow-up Bone marrow samples Slide 19 UNIVERSITY OF MODENA AND REGGIO EMILIA SINCE 1175 Working group Stefania Cerri Fabrizio Luppi Paolo Spagnolo Francesca Panico Luca Richeldi with precious feedback and suggestions from Giulia Grisendi Massimo Dominici