Stefania Cerri, Paolo Spagnolo, Fabrizio Luppi, Luca Richeldi

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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 dellApparato
Respiratorio Gaiato, 16 luglio 2011
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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

UNIVERSITY OF MODENA AND REGGIO EMILIA
Control
Collagen I
1. Bucala R., et al. Molecular Medicine, 1994
1(1)71-81
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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

UNIVERSITY OF MODENA AND REGGIO EMILIA
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Fibrocytes markers
UNIVERSITY OF MODENA AND REGGIO EMILIA
Bellini A., Mattioli S., Laboratory Investigation
2007 87858-70
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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
  aging

UNIVERSITY OF MODENA AND REGGIO EMILIA
Herzog EL., Bucala R., Experimental Hematology
2010 38548-56
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IDIOPATHIC PULMONARY FIBROSIS (IPF)
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
ATS/ERS/JRS/ALAT IPF GUIDELINES 2011
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Pathogenesis of IPFAbnormal wound healing model
UNIVERSITY OF MODENA AND REGGIO EMILIA
Selman M., Ann Intern Med 2001 134136.
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UNIVERSITY OF MODENA AND REGGIO EMILIA
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Circulating fibrocytes in human fibrotic
interstitial lung disease
UNIVERSITY OF MODENA AND REGGIO EMILIA
UIP usual interstitial pneumonia NSIP
non-specific interstitial pneumonia
Mehrad et al. Biochem Biophys Res Commun 2007
353104-8.
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Circulating fibrocytes and IPF prognosis
UNIVERSITY OF MODENA AND REGGIO EMILIA
Fibrocytes defined as CD45 and Coll-1 cells
among live PBMC
Moeller et al. Am J Respir Crit Care Med 2009
179588-94.
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Circulating fibrocytes and IPF prognosis
UNIVERSITY OF MODENA AND REGGIO EMILIA
Fibrocytes defined as CD45 and Coll-1 cells
among live PBMC
Moeller et al. Am J Respir Crit Care Med 2009
179588-94.
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AGE MATTERS

• MSCs of ageing mice have decreased ability to
  differentiate

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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 FIBROSISA PROSPECTIVE STUDY
IL PROGETTO
UNIVERSITY OF MODENA AND REGGIO EMILIA
GR-2009-1607498
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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.

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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.

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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

UNIVERSITY OF MODENA AND REGGIO EMILIA
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Working group
Stefania Cerri Fabrizio Luppi Paolo
Spagnolo Francesca Panico Luca Richeldi with
precious feedback and suggestions from Giulia
Grisendi Massimo Dominici
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