Bando Ricerca Finalizzata 2009 – Ministero della Salute
Progetto Giovani Ricercatori
Fibrociti e cellule mesenchimali staminali
nella fibrosi polmonare idiopatica
Stefania Cerri, Paolo Spagnolo, Fabrizio Luppi, Luca Richeldi
Meeting DAI di Oncologia, Ematologia e Patologie dell’Apparato
Respiratorio
Gaiato, 16 luglio 2011
• Firstly described in 19941
UNIVERSITY OF MODENA
AND REGGIO EMILIA
Fibrocytes
• 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
Control
Collagen I
1. Bucala R., et al. Molecular Medicine, 1994; 1(1):71-81
SINCE 1175
• 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
UNIVERSITY OF MODENA
AND REGGIO EMILIA
Fibrocytes markers
SINCE 1175
• Fibrocytes have been described in several diseases in
which fibrosis occurs
– Asthma
– Skin scars and keloids
– Scleroderma
– Liver fibrosis
– Cardiac disease
– Renal fibrosis
UNIVERSITY OF MODENA
AND REGGIO EMILIA
Fibrocytes in health and disease
• Circulating fibrocytes may be increased in normal aging
Herzog EL., Bucala R., Experimental Hematology 2010; 38:548-56
SINCE 1175
Specific form of chronic, progressive fibrosing interstitial pneumonia of
unknown cause, occurring in adults and limited to the lungs.
UNIVERSITY OF MODENA
AND REGGIO EMILIA
IDIOPATHIC PULMONARY FIBROSIS (IPF)
SINCE 1175
SINCE 1175
UNIVERSITY OF MODENA
AND REGGIO EMILIA
Abnormal wound healing model
UNIVERSITY OF MODENA
AND REGGIO EMILIA
Pathogenesis of IPF
Selman M., Ann Intern Med 2001; 134:136.
SINCE 1175
Laurent GJ, PATS 2008
SINCE 1175
UNIVERSITY OF MODENA
AND REGGIO EMILIA
UIP: usual interstitial pneumonia; NSIP: non-specific interstitial pneumonia
UNIVERSITY OF MODENA
AND REGGIO EMILIA
Circulating fibrocytes in human
fibrotic interstitial lung disease
Mehrad et al. Biochem Biophys Res Commun 2007; 353:104-8.
SINCE 1175
UNIVERSITY OF MODENA
AND REGGIO EMILIA
Circulating fibrocytes and IPF prognosis
Fibrocytes defined as CD45+ and Coll-1+ cells among live PBMC
Moeller et al. Am J Respir Crit Care Med 2009; 179:588-94.
SINCE 1175
UNIVERSITY OF MODENA
AND REGGIO EMILIA
Circulating fibrocytes and IPF prognosis
Fibrocytes defined as CD45+ and Coll-1+ cells among live PBMC
Moeller et al. Am J Respir Crit Care Med 2009; 179:588-94.
SINCE 1175
AGE MATTERS
•
Ageing mice develop more fibrosis in response to Bleomycin, have more
fibrocytes
•
MSCs of ageing mice have
decreased ability to
differentiate
Xu J. et al. J Gerontol A Biol Sci Med Sci 2009
Mesenchymal stem cell engraftment in lung is enhanced in
response to bleomycin exposure and ameliorates its fibrotic
effects
Saline
Bleomycin
Ortiz LA et al. PNAS 2003; 100(14):8407-11.
Bleomycin + BM-MSC
MESENCHYMAL PROGENITOR CELLS
AS BIOMARKERS IN IDIOPATHIC
PULMONARY FIBROSIS:
A PROSPECTIVE STUDY
UNIVERSITY OF MODENA
AND REGGIO EMILIA
IL PROGETTO
GR-2009-1607498
SINCE 1175
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.
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.
• Total duration: 3 years
UNIVERSITY OF MODENA
AND REGGIO EMILIA
Study design
• 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
SINCE 1175
Stefania Cerri
Fabrizio Luppi
Paolo Spagnolo
Francesca Panico
Luca Richeldi
with precious feedback and suggestions from
Giulia Grisendi
Massimo Dominici
UNIVERSITY OF MODENA
AND REGGIO EMILIA
“Working group”
SINCE 1175
Scarica

since 1175