Stefania Cerri, Paolo Spagnolo, Fabrizio Luppi, Luca Richeldi
Meeting DAI di Oncologia, Ematologia e Patologie dell’Apparato
Respiratorio
Gaiato, 16 luglio 2011
Fibrociti e cellule mesenchimali staminali nella fibrosi polmonare
idiopatica
Bando Ricerca Finalizzata 2009 – Ministero della Salute
Progetto Giovani Ricercatori
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Fibrocytes
• Firstly described in 19941
• 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. 0.5% of circulating leukocytes
1. Bucala R., et al. Molecular Medicine, 1994; 1(1):71-81
Control Collagen I
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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
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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 agingHerzog EL., Bucala R., Experimental Hematology 2010; 38:548-56
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IDIOPATHIC PULMONARY FIBROSIS (IPF)IDIOPATHIC PULMONARY FIBROSIS (IPF)
Specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring in adults and limited to the lungs.
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Pathogenesis of IPFAbnormal wound healing model
Selman M., Ann Intern Med 2001; 134:136.
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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.
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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
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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
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
Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects
Saline Bleomycin Bleomycin + BM-MSC
Ortiz LA et al. PNAS 2003; 100(14):8407-11.
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MESENCHYMAL PROGENITOR CELLS AS BIOMARKERS IN IDIOPATHIC
PULMONARY FIBROSIS:A PROSPECTIVE STUDY
IL PROGETTO
GR-2009-1607498
Project aims
• Aim 1Measurement 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.
Project aims
• Aim 2Measurement 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.
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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
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“Working group”
Stefania CerriFabrizio Luppi
Paolo SpagnoloFrancesca Panico
Luca Richeldi
with precious feedback and suggestions fromGiulia Grisendi
Massimo Dominici