Programma Staminali - Ospedale San Raffaele

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Aggiornato al 10.10.09
DIVISION OF REGENERATIVE MEDICINE
INTERDEPARTMENTAL RESEARCH PROGRAM
STEM CELLS
FROM BASIC RESEARCH TO
CLINICAL EXPERIMENTATION
PROGRAM LEADER (ad interim):
GIULIO COSSU
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INDEX
1. INTRODUCTION
PAG. 3
2. PARTICIPATING INVESTIGATORS
PAG. 5
3. AIMS
PAG. 6
4. WORCKPACKAGE LIST
PAG. 7
5. WORK PACKAGES, MILESTONES AND DELIVERABLES
PAG. 8
6. TIME SCHEDULE
PAG. 22
7. REFERENCES
PAG. 24
8 GOVERNANCE
PAG. 25
9. PARTICIPATING UNITS (COMPONENTS, FUNDING AND
PUBLICATIONS 2005-2008)
PAG. 26
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2. INTRODUCTION
Aim of this program is the development and integration of research projects studying stem
cell biology and their ability to restore tissue integrity in pre-clinical models of genetic and acquired
diseases. Its final goal is to promote clinical translation of a number of these projects optimizing
chance of efficacy and minimizing risks for patients.
This is an exciting period for research in stem cell biology and translational medicine in
general: many research projects have been developed in pre-clinical models for the previous years
and are now facing the challenge of entering clinical experimentation. It has also become apparent
that the whole process, starting with gene discovery and continuing with the understanding of the
pathogenesis and the creation and use of animal (mainly mouse) models, is now much rapid than it
was only ten years ago.
At the same time it is perceived by the community that clinical translation is a critical step
and must be taken with all possible reliable predictions of efficacy and low risks for patients. We
have learned in recent years that one serious adverse events (Hacein-Bey-Abina et al. 2008), even
if unpredictable on the basis of thorough and rigorous pre-clinical work, may hamper the whole
field for years. It is probably worth to stress that the International Society for Stem Cell Research
(ISSCR) has recently published “Guidelines for clinical translation of stem cell research” (available
at isscr.org). These Guidelines were drafted by an international task force (Hyun et al., 2008) “to
help facilitate the responsible and timely development of clinically useful stem cell-based therapies
and to help minimize the potential harms to research subjects and patients”.
Within this overall scenario, our Institution has a prominent international role, mainly due to
pioneering work of congenital immune deficiencies (Aiuti et al. 2002), and many highly promising
projects ready for or already entering clinical trials. Moreover there are a large number of basic or
clinical research groups that are either directly involved in stem cell research, but at an earlier
stage of development, or provide invaluable expertise in cell and molecular biology, in immunology
and in imaging, just to name a few. These groups may be interested and involved in a large
Institutional program like this one, by contributing their expertise and, at the same time, benefiting
of the previous experience of those groups that are ahead towards clinical experimentation.
For this reason the program suffers of certain heterogeneity and will require a continuous
effort by all participants to progressively focus and refine the objectives. At the same time it offers a
great opportunity to put together many of the leading expertise of our Institution and create
synergies to achieve faster and safer clinical translation of our research.
As usual in this area, the program is divided in three main workpackages, basic, pre-clinical
and clinical, as well as in a number of milestones and deliverables that will have to be reached at
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the end of its three years duration. Moreover, because of its nature, a first overall evaluation of its
progress will be carried out one year after its start.
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3. PARTICIPATING INVESTIGATORS:
Aiuti Alessandro DRM
Bacchetta Rosa DRM
Bianchi Marco DGCB
Blasi Francesco DGCB
Bonini Chiara DRM
Brunelli Silvia DRM
Clementi Emilio DRM
Ciceri Fabio DRM
Cossu Giulio DRM
D’Alessio Silvia, DGCB
Del Maschio Alessandro
De Palma Michele DRM
Ferrari Giuliana DRM
Feischhauer Katharina DRM
Gabellini Davide DRM
Galli Rossella DRM
Gregori Silvia DRM
Gritti Angela DRM
Grohovatz Fabio ALEMBIC
Nadini Luigi DRM
Manfredi Angelo DRM
Meldolesi Jacopo DNS
Montini Eugenio DRM
Peretti Giuseppe
Piemonti Lorenzo
Politi Letterio
Previtali Stefano INSPE and DNS
Rama Paolo DNS
Roncarolo Maria Grazia DRM
Rovere Patrizia DRM
Villa Anna DRM
Zerbini Giampaolo DRM
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4 AIMS
Aims of this program are:
1.
To understand the mechanisms regulating the emergence of stem cells during
embryogenesis, their lineage and potency during tissue histogenesis and
regeneration. To understand how these mechanisms are perturbed in cancer
stem cells.
2.
To understand the mechanisms regulating survival, proliferation, migration and
differentiation of stem cells during tissue regeneration, either in situ or after
transplantation.
3.
To develop gene modification strategies for stem cells, by either providing a wt
copy of or repairing the mutated gene, or, otherwise providing a beneficial
function to the cell.
4.
To study the mechanisms regulating tissue damage and repair, including
inflammation, sclerosis, neo-angiogenesis and immune response and the
possible modulation of these processes.
5.
To test the efficacy of stem cell transplantation in small and (when possible) large
animal models of genetic and acquired diseases.
6.
To help developing all the steps required for clinical translation (GMP production
of stem cells, toxicology studies, submission of the protocol to the Ethical
Committee and to the Regulatory Authorities, etc.).
7.
To facilitate the start of clinical experimentation (patient recruitment, logistics,
data management, etc.).
It is obvious that these aims encompass all stem cell biology and clinical application and
thus they should not be intended as a whole to be achieved, but rather as a framework
where individual projects may find a logical pathway and develop interactions and
collaborations. More specific goals to be achieved, with a given stem cell type for a specific
disease are detailed in the following section.
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5. Workpackage list:
1. Biology of stem cells:
1a. Origin, lineage and potency of stem cells.
1b. Transplantation (or mobilization) of stem cells.
2. Pre-clinical models:
2a. Analysis and modulation of tissue damage and repair.
2b. Test of cell therapy in small and large pre-clinical models.
2c. Tracing of stem cells in vivo.
3. Clinical experimentation
3.a Projects entering clinical experimentation.
3b.Projects already in clinical trials (implementation and optimization).
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Workpackage 1:
Workpackage 1a: Origin, lineage and potency of stem cells.
1a1: G. Ferrari, F. Blasi: 1a: HSC asymmetric cell division and endocytosis/intracellular
segregation. Prep1 is a developmentally essential haplo-insufficient tumor suppressor (Ferretti,
2006). Transplantation experiments with hemizygous fetal liver cells induce tumors of all kinds,
mainly lymphomas. However, the LTR efficiency of Prep1- HSC is 1/200 than normal (Di Rosa,
2007). Comparison of the gene expression profiles of the wt and Prep1- highly purified HSCs
(sorted KSLA cells) shows several important gene-sets involved. One of these, deals with
intracellular transport, endocytosis, microtubules segregation, all of them connected to asymmetric
cell division. We are planning experiments to clarify the role of the individual intracellular transport,
endocytosis, microtubules segregation genes identified, in the Prep1- HSC phenotype.
1a2. F. Blasi: Prep1 and Meis in Leukemic Stem Cells.
Prep1 appears to normally balance the role of Meis1 in leukemogenesis, in particular in Leukemic
Stem Cells formation. In fact, among the genes up-regulated in Prep1- HSCs, the complete Meis1HoxA9 signature is present. Meis1-HoxA9 are two genes whose over-expression is oncogeneic,
and which are the determinants of leukemias induced by all the MLL-fusions.
Prep1 and Meis1 are highly homologous proteins, with great functional overlap, i.e. they can both
bind Pbx through the same interaction surface conferring the ability to bind DNA through the same
DNA sequences (Berthelsen, 1998). Moreover, the phenotype of the Meis1 K.o. mice and that of
the Prep1 hypomorphic mice (Azcoitia, 2005; Ferretti, 2006) is very similar: HSC defects,
oculogenesis and angiogenesis defects. However, Meis1 is oncogenic while Prep1 is a tumor
suppressor. We are therefore exploring the similarities and diversities of Prep1 and Meis1 in the
HSC and cancer SC, to understand the molecular basis of such a profound difference.
1a3. S. D’Alessio, F Blasi: Role of the urokinase receptor (uPAR) in mouse skin stem cells
proliferation and migration. The uPAR Ko mice have a delayed skin wound healing and are
protected from skin carcinogenesis. This is due to a variety of biochemical abnormalities of the
uPAR Ko keratinocytes, for example the inability to activate their EGF-Receptor (D’Alessio et al.,
2008). However, studies of the Skin Stem Cells show abnormalities in their number, migration and
proliferation. We are therefore analyzing in detail the role of uPAR in skin stem cells using also
tracer-mice in addition to the uPAR K.o.
.
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1a4. J Meldolesi: REST/NRSF- mediated regulation of leptomeninge derived neural stem cell
differentiation. We want to use a new type of stem cells recently identified in the rat leptomeninges
that have great tendency to differentiate into neurons. These cells offer the possibility to investigate
the role in the differentiation of the transcription repressor NRSF/REST and possibly also of other
factors. Based also on our recent results in PC12 cells we will consider also the possibility that
processes that take place in parallel in the differentiating cells, such as the appearance of
neurosecretion and neurite sprouting, are differentially regulated. Another interesting question will
be whether stimulation of the differentiating cells by various means interferes with differentiation
and by what mechanism.
1a5. G. Cossu: Origin and fate of pericytes. Inducible Alkaline Phospatase/Cre-ER mice have been
produced (AP is a marker of pericytes in post-natal striated muscle: Dellavalle et al. 2007) and
crossed to Rosa26 floxed mice. We showed that pericytes contribute to cardiomyocites and
skeletal myofibers during post-natal growth and now plan to cross these mice with dystrophic mice
(to test the role of pericytes in muscular dystrophy) as well as with inducible Akt, Notch or Bmi1
mice to alter proliferation and differentiation of these cells in vivo. Additionally, experiments are
performed to test reciprocal recruitment of pericytes to skeletal muscle and of skeletal myoblasts to
a pericyte fate in vitro.
1a6. V. Broccoli: human iPS. Aims are: 1) Characterization of the stability of long-term human iPS
cell cultures; ii) Optimization and validation of different cellular sources for reprogramming. iii)
Defining growth factor requirements for iPS cells derived by genetic reprogramming. Mouse and
human iPS cells have been generated from different type of both embryonic and adult cells.
However, it remains unclear their optimal growth factor requirement, their long-term stability,
normal caryotype content, proliferation ability and developmental potential. Thus, we will compare
human iPS cell cultures from different sources for long-term culture potential assessed by
phenotypic and molecular analysis (In collaboration with J. Adjaye). The transcripome of several
different iPS human cell lines will be compared to evaluate the stability of the pluripotent state in
long-term culture (in collaboration with J. Adjaye). Further, different source of mouse or human cell
types will be employed to identify the ideal cellular substrate for reprogramming. Finally, genetically
reprogramming will be carried out in the presence of different growth factor containing media in
order to evaluate whether fibroblast de-differentiation can give rise to iPS with a different
pluripotent state and mimicking either naïve ES or EPI cells.
1a7. L. Piemonti: Renewing beta cells by creation of insulin producing cells from stem cells.The
present program inquires the possibility to isolate stem cells from adult/fetal tissue and to establish
their differentiation potential toward insulin-secreting cells. We propose different approaches: 1) to
study the potential of CD133+ intra-pancreatic stem cells to be differentiated into beta cells. The
proposal is based on the identification and isolation of a CD133+/EpCam+/Ca19.9+/CD73- tissue
stem cells from digested human pancreas; 2) to study the potential of induced pluripotent stem
cells (IPS) to be differentiated into beta cells. The proposal is based on the availability of human
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IPS in the Institute (Broccoli) and of defined protocols of differentiation of ES cells to beta cells; 3)
to study the potential of amniocytes to be differentiated into beta cells. The proposal is based on
the confirmation in our hand of the existence of a subpopulation of ckit positive human amniocytes.
These cells were described to posses the ability to differentiate in all the embryonic lineages
including endoderm; 4) to identify factor/s and pathways able to modulate the differentiation of
pancreatic precursor by studying the expression of transcriptional factor involved in pancreas
development in pancreatic cancer cell. The proposal is based on our evidence that pancreatic
cancer cell express transcriptional factors involved in pancreas development
1a8. L. Naldini, G. Cossu, V. Broccoli: IPS for mesoderm progenitors. We plan to induce IPS from
fibroblasts of Limb Girdle 2D dystrophic patients (who apparently lack AP+ pericytes and to induce
the resulting IPS to a Flk+, circulating mesoderm progenitor, that could be delivered systemically.
Myogenic differentiation would be then induced in these progenitors by transduction with a
lentivector expressing an inducible ER-MyoD.
1a9. S. Brunelli: Origin and fate of endothelial progenitor cells in muscle development and
regeneration. We have generated transgenic mice expressing tamoxifen inducible CRE-ERT2
under the control of VE-Cadherin regulatory sequence (Hisatsune et al. 2005). Mice have been
crossed to ROSA26-LacZ and ROSA26-EYFP. When CRE activity has been induced at embryonic
day E8.5, we observed presence of EYFP or LacZ positive myofibers until postnatal day 3. In
addition FACS sorting of EYFP positive cells at E14.5 allowed us to obtain EYFP myoblasts in
vitro, positive also for VE-cadherin. Adult contribution of embryonic endothelial progenitors to new
myofibers and neo-angiogenesis can be observed only when acute damage is induced. We will
further extend the investigation also in chronic muscle damage (alpha-SG KO mice) and in mouse
model where the myogenic line of somitic origin is deficient (Pax7KO mice).
Workpackage 1b: Transplantation (or mobilization) of stem cells
1.b1. A Del Maschio: Imaging of migrating stem cells. Magnetic resonance imaging (MRI), which
represents one of the safest imaging modality in clinic, has now become a powerful tool for cellular
imaging. Cellular imaging can be defined as the non-invasive and repeatable imaging of targeted
cells, which requires proper labeling of cells with appropriate MR contrast agents. Iron oxide
nanoparticles based contrast agents are the most frequently used for cellular imaging and tracking
purposes, because of the strong contrast effect provided and the demonstrated high
biocompatibility and biodegradability. The first aim of our experiments will be to apply the labeling
methods based on iron nanoparticles (Manfredi et al. J Immunol 2008) to different stem cells
lineage with a careful assessment of the different aspects concerning the safety, along with the
evaluation of the effectiveness of the labeling procedure for the in-vivo MRI tracking. Both small
particles of iron oxide (SPIO) and ultra-small particles of iron oxide (USPIO) contrast agents will be
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used for labeling experiments in order to find the better setting considering safety and contrast
effects. Moreover, the technique of reporter gene will be arranged to engineer stem cells in order to
obtain an over-expression of the ferritin receptor responsible of endogenous iron sequestration,
with the aim of create stem cells with an intrinsic T2 effects, overcoming the problems linked to
exogenous labeling agents. A further objective will be to develop quantitative automatic or
semiautomatic software for imaging analysis and innovative in-vivo MR imaging methods of
labeled cells, to move from a mainly qualitative imaging allowed by the classic T2w and T2*w
sequences, toward a quantitative approach based on the improvement of a positive MR imaging
taking advantage from the spatial variation in the Larmor frequency of the nuclear spins induced by
iron agents (Cunningham et al. Magn Reson Med 2005; Mani et al. Magn Reson Med 2006).
1b2: M Bianchi: HMGB-1 induced migration of stem cells: HMGB1 is a highly conserved nonhistone DNA-binding protein. In human cells, HMGB1 localizes in the nucleus, where it regulates
gene expression. HMGB1 acquired further notoriety after it was realized that it can be secreted to
act as a signal of tissue and cell damage. RAGE (receptor for advanced glycation end products)
and toll-like receptors (TLR) have been identified as the receptors by which extracellular HMGB1
induces its biological functions. The identification of HMGB1 as the signal of tissue damage should
be exploited to develop applications in the field of tissue regeneration. In the last few years our
laboratory documented that HMGB1 acts as a signal of damaged tissue to stimulate
mesoangioblasts to initiate cell division, cell movement and replacement of injured tissue. In
particular, we found that HMGB1 recruits mesoangioblasts to damaged tissue, induces migration
and proliferation, and determines the loss of cell-cell contacts in endothelial monolayers in vitro.
Similar effects occurred in mice in which recombinant HMGB1 was slowly released from implanted
beads. Furthermore, we showed that both healthy and dystrophic muscles express HMGB1, and
that the protein is much more abundant in dystrophic muscle (Palumbo R. et al. J Cell Biol 164:
441-9, 2004). More recently we showed that the activation of the transcription factor NF-κB by
HMGB1 is necessary for fibroblast and mesoangioblast migration (Palumbo R. et al. J Cell Biol 19:
33-40, 2007). Mesoangioblasts in which th NF-κB signaling pathway was impaired lost their ability
to migrate into dystrophic muscle. Based on these previous results we will investigate in vivo
whether RAGE and TLR are involved in mesoangioblast migration stimulated by HMGB1, and if so,
how. To dissect the contribution of these receptors in mesoangioblast migration mediated by
HMGB1, we plan to isolate mesoangioblasts from RAGE knockout mice and from mice deficient for
the TLR adaptor molecule MyD88, which is necessary for most types of TLR signaling.
1b3: M. De Palma, L. Naldini: Biology of Tie2-expressing monocytes (TEMs), tissue remodeling
and angiogenesis. TEMs are recruited to sites of angiogenesis and their elimination in mouse
tumor models inhibits tumor angiogenesis, indicating that these cells play an important
proangiogenic role in tumors. Because TEMs express a broad array of proangiogenic factors and
tissue-remodeling proteins, they might be used to restore angiogenesis and facilitate organ
regeneration. Preliminary data indicate that injection of TEMs in the infaRcted mouse myocardium
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improves peri-infarct neovascularization and perfusion. We will study whether TEMs also
participate in skeletal muscle regeneration and whether they could be used to improve dystrophic
muscle regeneration by injected mesoangioblasts. TEMs will be isolated from either mouse or
human blood and co-injected together with mesoangioblasts intra-muscularly or intra-arterially.
1b4. A. A. Manfredi, P. Rovere-Querini: Macrophage response to the injury of mesodermic tissues.
Tissue injury elicits a complex homeostatic response, in which innate immune cells play a key role
both in the disposal of tissue debris and in the generation of signals that activate local stem cells
and attract progenitors from the circulation. Moreover, innate cells play a crucial role in shaping
the outcome of acquired, T-cell dependent immune responses, which contribute to the eventual
outcome of injury (chronic inflammation with eventual wasting, fibrosis of regeneration). We will
dissect the role of innate immune cells, with particular attention to polarized macrophages and
dendritic cells in models of mesodermic tissue injury, with particular attention to vessels, serosal
membranes and skeletal muscle.
1b5. S Brunelli: Necdin to promote muscle regeneration. We have previously shown that Necdin
increases myogenin expression, accelerates differentiation, and counteracts myoblast apoptosis.
In addition necdin protects skeletal muscle from tumor-induced muscle atrophy by inhibiting the
action of TNFalpha. We are now investigating the signalling pathways that mediate necdin action,
focussing in particular on the interaction of necdin with p53 and TNFα.
1b6. G Cossu: NFIX to promote muscle regeneration. NFIX is a crucial regulator of fetal
myogenesis, playing a central role in transcriptional control of skeletal myogenesis, by activating
fetal while repressing embryonic genes. We have generated transgenic mice over-expressing NFIX
and obtained conditional mutants to study the role of this gene in post-natal myogenesis,
regeneration and dystrophy.
1b7. E Clementi: NO to promote angiogenesis and muscle regeneration. The project aims at
identifying novel therapeutic approaches to muscular dystrophy by identifying key molecular events
or signaling molecules in muscle development that can be targeted by pharmacological tools.
Great emphasis in the study is on bioenergetics of skeletal muscle and on pro-angiogenetic events
that can enhance muscle repair. One candidate therapeutic approach, involving NSAIDS and NO
donors, is already in phase II clinical experimentation.
1b8. K Fleischhauer: Immunogenetics of hematopoietic stem cell transplantation. Polymorphism of
immune-related (IR) genes plays a pivotal role of the outcome of allogeneic tissue transplantation.
We are studying the role of non-permissible mismatches for human leukocyte antigen (HLA)
molecules, as well as genome-wide IR gene polymorphisms,
in the setting of allogeneic
hematopoietic stem cell transplantation (HSCT). Particular focus is made on the role of T and NK
cell alloreactivity in promoting graft versus leukemia activity after allogeneic HSCT, and on the
development of new approaches to exploiting gene polymorphisms for the assessment of
hematopoietic chimerism post-transplant.
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1b9. R Bacchetta, MG Roncarolo, S Gregori: Tr1 cell therapy to improve immuno-reconstitution
and prevent GvHD after HSCT. Tr1 cells are induced in vivo and in vitro after antigen(Ag)-specific
stimulation in the presence of either exogenous or DC-derived IL-10. Tr1 cells play a key role in
maintaining tolerance to self and non-self Ags, including allo-Ags. We have developed a method to
generate alloAg-specific Tr1cells ex-vivo using either monocyte+IL-10 or tolerogenic DC, termed
DC-10, to be used a cell therapy in vivo. A clinical trial of adoptive Tr1 cell therapy to promote
immune-reconstitution and prevent GvHD in onco-hematological patients transplanted with haploidentical HSCT is currently ongoing.
1b10. R. Bacchetta, S. Gregori, MG. Roncarolo, K. Fleishhauer: Study of cellular and molecular
signature predictive of allogenic HSCT outcome. Tr1 cells are present in peripheral blood of
tolerant patients with mixed persistent chimerism post HSCT. We will characterize Tr1 cells
developed in vivo in tolerant patients. In addition, by extensive genomic studies we will identify
genes that can favor the induction of transplantation tolerance. By correlating the biological and
genomic data we will define molecules that can have predictive values for the HSCT outcome.
1b11. S. Gregori: Role of tolerogenic DC-10 in promoting tolerance after hemetopoietic stem cell
transplantation (HSCT). Tolerogenic DC-10 can be differentiated in vitro in the presence of IL-10
and are present in vivo. DC-10 represent a new subset of tolerogenic DC that secrete high levels
of IL-10, express tolerogenic molecules, and induce Tr1 cells in vitro.
We are currently
investigating the frequency and function of DC-10 in vivo in patients after HSCT and their role in
promoting tolerance via induction of Tr1 cells.
1b12. S. Gregori: Immune role of HLA-G at donor/host interface in allogeneic stem cell
transplantation (HSCT). HLA-G, a non-classical HLA class I molecule, plays a central role in
promoting tolerance in fetus-maternal tolerance. HLA-G modulates inhibits cytotoxic activities of
NK and CTLs and proliferation of allo-specific T-cell. HLA-G expression is induced after allogeneic
transplantation in vivo and HLA-G expression by CD4+ T cells during MLR inhibits allo-specific Tcell proliferation, suggesting that HLA-G plays a role in modulating allo-responses. A 14bp
insertion in the 3’ untranslated region (UTR) of HLA-G, in linkage disequilibrium with a second
polymorphism in the 5’UTR, is correlated with a increased HLA-G mRNA and has been associated
with immunological tolerance in pregnancy and autoimmunity. We aim at elucidating the role of
HLA-G and its polymorphisms in controlling the immune response after allogeneic HSCT.
1b13. MG. Roncarolo, M. Battaglia: Rapa expanded CD25+ Treg cell therapy to improve immunoreconstitution and prevent GvHD after HSCT. Naturally occurring CD4+CD25+FOXP3+ Treg cells
are present in very low number in peripheral blood mononuclear cells but can be expanded in vitro
in the presence of rapamicin. We are currently testing appropriate methods suitable to isolate the
starting Treg population to be expanded and subsequently transferred in vivo
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Workpackage1: Milestones
1a1: Identification of the endocytic pathway(s) involved in asymmetric HSC division.
1a2: Identification of the molecular competition mechanism distinguishing the oncosuppressor
Prep1 from the oncogenic Meis1 in normal leukemic stem cells homeostasis.
1a3: Understanding the role of uPAR in skin stem cells biology.
1a4: Identfication of the role of NRSF/REST in neuronal differentiation
1a5: Definition of the role of pericytes in muscle growth, repair and in dystrophy.
1a6: Assessing mouse and human iPS growth factor requirements, long-term
stability and optimal cellular sources
1a7:
Identification of a renewable source of cells to be used to increase the transplantable beta
cell mass in diabetic patients.
1a8: Generation of a circulating, mesoderm inducible normal progenitor. Generation of a
circulating, myogenically inducible, LG2D dystrophic, genetically corrected progenitor.
1a9: Definition of the role of endothelial progenitors in muscle growth, repair and in dystrophy
1b1: Development of NMR based protocols for cell tracking in vivo
1b2Identification of the relative role of RAGE and TLR4 in mesoangioblast migration at the site of
tissue damage
1b3: Role of TEMs in skeletal muscle regeneration. Combined cell therapy of dystrophic muscle by
TEMs and mesoangioblasts.
1b4: Identification of molecules that regulate the interaction between polarized macrophages and
progenitors in injured skeletal muscle. Establishment of mouse models of vessel, muscle
and peritoneal injury defective of candidate protective/deleterious gene products.
1b5: Definition of the role of Necdin in muscle regeneration.
1b6: Definition of the role of NFIX in muscle regeneration.
1b7: Novel NO-based protocols for cell transplantation and tissue repair.
1b8: Novel protocols for HLA-mismatched HSC transplantation.
1b9: To determine Tr1 cell therapy safety and efficacy in promoting immune-reconstitution and
preventing GvHD, and extend their application to other disease settings.
1b10: Definition of predictive cellular and molecular signature for transplantation tolerance.
1b11: To determine the biological role of DC-10 in promoting tolerance after HSCT.
1b12: To define the role of HLA-G and its polymorphisms in modulating immune response after
HSCT.
1b13: Completion of pre-clinical protocol to obtain CD4+CD25+ Treg cells expanded in vitro with
rapamicin, and definition of safety clinical trial in HSCT.
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Workpackage 2. Pre-clinical models
Workpackage 2a. Analysis and modulation of tissue damage and repair.
2a1: S. Brunelli: The role of necdin in mesoangioblast function. We have isolated and
characterized adult muscle-derived mesoangioblasts from wt, Ndn-/- mice and necdin gain of
function mice (MlcNec) (Deponti et al, 2007), and we have also generated a line of MABs
constitutivelly overexpressing Ndn, by infection with a lentiviral vector (NdnMABs). Overexpression
of Ndn in vitro increases the differentiation ability of MABs, and inhibit cell death induced by
several apoptotic stimuli. To study the relative contribution of these cells to muscle regeneration in
vivo we have performed intra-muscular and intra-arterial injections of NdnMABs and control
mesoangioblasts in the dystrophic murine model (alpha-sarcoglycan null mice). Preliminary data
showed that muscle injected with NdbMABs showed a greater restoration of the alpha-SG
expression. We will extend the analysis on a long term muscle reconstitution, and studying the
effect of the transplantation of these modified mesoangioblasts on morphological, biochemical and
physiiological parameters.
2a2 G. Cossu: The role of NFIX in satellite cell and mesoangioblast function. Satellite cells and
mesoangioblasts have been derived from NFIX over-expressing or null mice and their ability to
contribute to regeneration of injured or dystrophic skeletal muscle will be tested.
2a3: E Clementi: role of NO in muscle angiogenesis and regeneration.
The project aims at
identifying novel therapeutic approaches to muscular dystrophy by identifying key molecular events
or signaling molecules in muscle development that can be targeted by pharmacological tools.
Great emphasis in the study is on bioenergetics of skeletal muscle and on the role of NO as an
angiogenetic factor. One candidate therapeutic approach, involving NSAIDS and NO donors, is
already in phase II clinical experimentation.
2a4: G. Zerbini: Role of EPC in diabetes. Endothelial progenitor cells and vascular disease in type
1 diabetes. The long-term goal of our studies is to learn whether endothelial progenitor cells
(EPCs) can be used in subjects with type 1 diabetes as trustworthy informant of overall vascular
status and occurrence of specific events in the retina. We observed that patients with long duration
of type 1 diabetes and suboptimal glycemic control a number of circulating EPCs lower than in
matched control subjects. We will define an “EPCs profile”, including (i) number of circulating EPC;
(ii) circulating levels of mobilizing cytokines, (iii) ability of circulating EPCs to form endothelial
colonies in vitro, and (iv) indices of attrition as measured by senescent cells and telomere
shortening in the colonies formed in vitro.
2a5: G Peretti: Tissue engineering for generating neo-cartilage and tendons. Muscle-derived stem
cells have been recently demonstrated to have chondrogenic potential (Kuroda R, 2006) and this
can be enhanced by VEGF blocking with soluble Flt-1 gene transfer.We will investigate the
chondrogenic potential of human mesoangioblasts under standard chondrogenic conditions (TGF-
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β3 or BMP-4 containing medium, low oxygen tension, etc.), with VEGF blocking in order to prevent
angiogenesis and consequently osteogenesis, once implanted in vivo. Micromass pellet culture
(Barbero A, 2004) and transwell culture (Murdoch AD, 2007) will be used to direct mesoangioblasts
toward a chondrogenic phenotype in the first task of the project. Bone marrow-derived hMSCs will
be used as a control. If the first task will be successful we will couple this method to tissue
engineering techniques by using custom-made biocompatible scaffolds in order to engineer
clinically relevant chondral, ostechondal and meniscal fibrocartilaginous grafts. Engineered
mesoangioblast-based grafts will be assessed after in vitro and nude mice culture.
2a6: L. Piemonti, Tissue remodeling of somatic cell therapy with pancreatic islet. Novel approaches
are needed to improve islet survival either immediately after transplantation, either in the long term.
We propose to a) Improve islet transplantation outcome by cotransplantation of islets and feeder
cells using mesenchymal stem cells as feeder cells. The proposal is based on preliminary data
showing that a large number of mesenchymal stem cells with proliferative capacity (Sordi et al.
2005) are retrieved in islet and non-islet fractions obtained from pancreas digestion. When
cotransplated with pancreatic islets, pancreatic MSC favour survival and function of transplanted
tissue (Sordi et al, submitted). b) Study bone marrow as site for islet transplantation. Survival of
both syngeneic and allogeneic islet grafts in the liver is sub-optimal in the mouse model (Melzi et al
2007). We propose the bone marrow as an alternative site because of its accessibility, its
environment rich in stem cells, and its potential for revascularization. Our data show that islets
survive exceptionally well in mice, when transplanted into the bone marrow (Cantarelli et al,
submitted).
Workpackage 2b. Test of cell therapy in small and large pre-clinical models.
2b1: Cossu: Cell therapy for Limb Girdle Muscular Dystrophy 2D. Alpha-sarcoglycan (a-SG)
null/SCIDbg mice and a lentivector expressing humana-SG have been produced. Mesoangioblasts
are being derived from patients but this proofs to be difficult (lack of AP perictyes as a possible
feature of this dystrophy. Thus IPS (see 1a6) are being generated as an alternative source of
donor stem cells.
2b2: Cossu: Reversible immortalization and Artificial Chromosome transfer for DMD cell
therapy. Human Artificial Chromosomes (HAC) allow transfer of the whole dystrophin locus
(Hoshiya et al. 2008) in mesoangioblasts from Duchenne patients. Transfer is inefficient and
requires selection that would lead primary human cells to senescence. To overcome this problem
we have reversibly immortalized with floxed lentivectors expressing human telomerase and Bmi1
both normal and DMD mesoangioblasts that maintain a non transformed, differentiation competent
phenotype. After HAC-Dys transfer, floxed vectors will be excised and cells transplanted into
mdx/SCID mice to test reconstitution of human muscle in vivo.
16
2b3: S. Previtali: Cell therapy for Congenital Muscular Dystrophy (CMD). CMD is
characterized by progressive wasting muscular dystrophy, dysmyelinating neuropathy and CNS
abnormalities. The most frequent form is due to mutations of the LAMA2 gene encoding the
laminin alpha2 chain, which forms merosin the predominant laminin isoform of muscle and nerve
basement membrane. The overexpression of mini-agrin, a cross-linker molecule that allows
reconnection of the basement membrane to the resident cells, showed amelioration of CMD in
animal models. We want to explore a cell therapy approach to deliver mini-agrin into the diseased
tissues. Mesoangioblasts have been infected with lentivirus vectors carrying a mouse mini-agrin
gene. Mesoangioblasts synthesize and secrete mini-agrin in vitro and in vivo. We will evaluate
effects of mini-agrin transduced mesoangioblast in 2 mouse models of CMD (Dy2J and Dy3K) to
prevent and rescue muscular dystrophy and peripheral neuropathy.
2b4: D. Gabellini: Cell therapy for FSH Muscular Dystrophy. Satellite cells and
mesoangioblasts are being derived from FRG1 over-expressing mice (Gabellini et al. 2006). Their
muscle differentiation capability and their ability to contribute to regeneration of dystrophic skeletal
muscle will be tested. Lentiviruses with an shRNA specific for FRG1 have been produced to
knockdown FRG1 on stem cells before transplantation. FRG1/SCIDbg will be generated in order to
test mesoangioblasts derived from FSHD patients.
2b5: G. Peretti: Neo-cartilage implants. According to our previous experience with large
animal models (Peretti GM, 2006) we will test the potential of the engineered grafts by implanting it
in orthotopic chondral, osteochondral and meniscal defects in pigs knees. As long as the zonal
architecture of the menisci implies that the inner part resembles hyaline cartilage while the outer is
more fibrous and vascularized, an interesting point to be addressed will be whether a differential
scaffold seeding with VEGF-blocked cells in the inner part and wild type cells in the outer part
would be beneficial in term of graft in vivo function, integration and survival.
2b6: S. Gregori, R. Bacchetta: Human IL-10-producing Tr1 cell therapy in pre-clinical
models of GvHD. A pre-clinical model of human GvHD in rag2-/-gc-/- mice has been developed.
This model will be used to test the in vivo function of in vitro differentiated Tr1 cells or LV-IL-10transduced T cells.
2b7: R. Bacchetta: FOXP3-transduced Treg from IPEX patients in pre-clinical model of
GvHD. Patients affected with IPEX have mutation in the FOXP3 gene, a transcription factor
essential for the differentiation and function of CD4+CD25+ Treg cells. These cells, although
present, are dysfunctional in IPEX patients. LV-mediated gene transfer of FOXP3 is able to confer
suppressive activity to naïve and memory T cells. We are currently testing the feasibility of LVmediated FOXP3 gene transfer in FOXP3 mutated cells. The activity of FOXP3-transduced cells
will be validated in a pre-clinical model of human GvHD in rag2-/-gc-/- mice.
Workpackage 2c. Tracing stem cells in vivo.
17
2c1: F. Grohovaz: Alembic facility: The available microscopy approaches will allow the
study of cellular functions in live cells as well as the ultrastructural analysis of the integration of
stem cells in host tissues. Different bright field and confocal approaches are available to meet the
various requirements for single cell, long term imaging under a controlled environment. High
throughput, high content imaging approaches are also available to simultaneously perform a broad
range of cellular and subcellular assays within the same cells. Electron microscopy approaches
can complement live cell studies with the morphological and immunolabeling analysis of cells and
tissues. A specific opportunity is offered by the use of the EM energy filter: microanalysis of a
specimen can be performed by electron energy loss spectra (EELS) and by electron-spectroscopic
imaging (ESI), thereby obtaining ultrastructural maps of specific elements (e.g. identification of
magnetically labeled Stem Cell within tissues even when the number of atoms is greatly reduced).
2c2: A. Del Maschio: MRI cell tracking. The technique of MRI cell tracking developed
should be directed towards the application in-vivo in different animal model of stem cell based
therapy, using a small bore 7T magnet (Bruker biospin), to understand the correlation between
MRI findings and therapeutic effects, as well as to investigate the spatio-temporal dynamics of in
vivo stem cell-tissue interactions and the local tissue vascular changes (neovascularization,
inflammation) occurring around the site of stem cells engraftment using blood pool contrast agents.
These data should be very useful for the development of more effective MR-guided cell therapy
protocols in the future.
2c3: L.S. Politi: Stem Cell tracking in vivo upon transplantation. Magnetic Resonance (MR)
based monitoring of magnetically labeled Somatic Stem Cell (SSC) transplantation, homing and
long-term persistence into target organs may provide critical information for development and
interpretation of SSC transplant approaches. Further, in vivo monitoring of gene expression would
contribute to the development of gene therapy approaches. Contrast media and newly developed
MR reporter genes and gene transfer vectors will be optimized for SSC tracking and then
employed to monitor SSC fate upon transplantation and gene expression in vivo.
Workpackage 2: Milestones:
2a1: Efficiency of muscle regeneration by Necdin over-expressing cells
2a2: Efficiency of muscle regeneration by NFIX over-expressing cells.
2a3: Preclinical and early clinical efficacy of NO in muscle angiogenesis and regeneration.
2a4: Role of EPC in diabetes
2a5: Chondrogenic potential of human progenitors under chondrogenic conditions.
2a6: Implementation of protocols for islet transplantation
2b1: Pre-clinical efficacy of human progenitor cell transplantation in LGMD2D/SCIDbg mice
2b2: Pre-clinical efficacy of transplantation or reversibly immortalized human mesoangioblasts,
HAC-Dys transduced, in mdx/SCID mice.
18
2b3: Pre-clinical efficacy of mini-agrin transduced mesoangioblasts in CMD animal models: effects
on skeletal muscle and peripheral nerve.
2b4: Pre-clinical efficacy of mouse mesoangioblasts transplanted in FRG1 mice and of human
FSHD mesoangioblasts transplantation in FRG1/SCIDbg mice.
2b5: Potential of the engineered grafts by implantation in orthotopic chondral, osteochondral and
meniscal defects in pigs knees.
2c1: Development of high resolution cell imaging.
2c2: Protocols for MRI based cell tracking in vivo.
2c3: Demonstration of efficient cell tracking after transplantation.
Workpackage 3: Clinical application
Workpackage 3a. Projects entering clinical experimentation
3a1: Y Torrente, F Ciceri, G Cossu: A single centre, prospective, non-randomized study:
“Outcome measures validation study for children affected by Duchenne Muscular Dystrophy
(DMD)”. Thirty DMD patients (with a sibling) and thirty controls, aged 5-10 will be tested
periodically for force of contraction and motility in order to create a data base and a single-patient
pattern. Three of these patients will continue with the protocol in 3a2.
3a2: G Cossu, Y Torrente, F Ciceri: A phase I “Allo-transplantation of donor
mesoangioblasts in DMD”. Three Duchenne pediatric patients will be transplanted intra-muscularly
and then intra-arterially with escalating doses of normal mesoangioblasts from an HLA-identical
donor, under a regime of immune suppression. Primary end-point: safety.
3a3: L Piemonti. A single centre, prospective, randomised study: “Pancreatic Islet
Autotransplantation With Completion Pancreatectomy in the Management of patients with high risk
for pancreaticojejunostomy after Whipple Resection.” Twenty selected patients undergoing
Whipple resection that are considered high risk for pancreaticojejunostomy disruption (eg, small
pancreatic duct, soft pancreas) will be randomized to receive pancreaticojejunostomy or
preemptive total completion pancreatectomy and islet autotransplantation. Primary end-points:
mortality, surgical morbidity, diabetes development.
3a4: F.Ciceri: Development of new strategies for bone marrow stem cell procurement
through the use of new drugs in combination with known growth factors. In particular, Plerixafor, a
partial agonist of the alfa-chemokine receptor CXCR4, has been found to be a strong inducer of
"mobilization" of hematopoietic stem cells from the bone marrow to the bloodstream as peripheral
blood stem cells. Peripheral blood stem cell mobilization, which has become extremely important
as a source of hematopoietic stem cells for transplantation over the past 10 to 15 years, is
generally performed using the cytokine drug G-CSF, but is ineffective in around 15 to 20% of
19
patients. Plerixafor offers clinical promise as a drug for peripheral blood stem cell mobilization, and
has recently completed Phase 3 clinical trials. It is not yet in routine clinical use. Plerixafor has
orphan drug status in the United States and European Union for the mobilization of hematopoietic
stem cells. It was approved by the U.S. Food and Drug Administration for this indication on
December 15, 2008
Workpackage 3B. Projects already in clinical trials (optimization)
3b1: P Rama: Autologous fibrin-cultured limbal stem cells transplantation.The cornea epithelia
integrity is maintained by the centripetal migration of stem-cell-derived transient amplifying cells
derived from the corneal stem cell located in the limbus, the narrow transitional zone of the ocular
surface located between the cornea and the bulbar conjunctiva. Diseases which involve the limbus,
such as ocular burns, are characterised by depletion of limbal cells thereby leading to corneal reepithelialisation by bulbar conjunctival cells. This abnormal wound healing induces
neovascularisation, chronic inflammation and stromal scarring with visual loss. Allogeneic corneal
grafting cannot be successful in these patients, unless the limbal stem cell population has been
restored by limbal transplantation. Between 1998 and 2007 we performed 125 transplantations of
autologous limbal stem cells cultivated on 3T3-J2 and fibrin on 112 patients with limbal stem-cell
deficiency. The overall results, after one or more procedures, were: 76.64% success, 13.08%
partial success and 10,28% failure. No failures were reported after one year. The procedure
appears safe and stable over time.
3b2: L Piemonti, L. Guidotti: Bone marrow as an alternative site for islet transplantation. Survival of
both syngeneic and allogeneic islet grafts in the liver is sub-optimal in the mouse model (Melzi,
Mercalli et al 2009 in press). Possible alternatives to the liver as a site for islet engraftment include
the spleen, omentum, pancreas, and muscle. We proposed the bone marrow as an alternative site
because of its accessibility, its environment rich in stem cells, and its potential for
revascularization. Our preliminary data show that islets survive exceptionally well in mice, when
transplanted into the bone marrow. The issues with respect to clinical applicability surround safety
which will be explored.
3b3: F Ciceri: Development of new pharmacologic and cellular platforms to allow allogeneic SCT
from alternative donors. The major limitation in offering a HSCT to any patient in need is the
availability of a marrow donor. Over the last decades, alternative donors such as family
mismatched up to partially incompatible (haploidentical) and stem cells derived from cord blood
have been pioneered in the field of SCT with very promising results. The availability of new
immunosuppressants (i.e. rapamycin) and a better knowledge on the immunological mechanisms
20
driving graft-versus-host disease and host-versus-graft have favoured a wider application of these
technologies. This will eventually allow to offer to almost 100% patients the option of cure through
HSCT. Results on the use of genetically engineered donor lymphocytes with the suicide gene
HSV-tk have been recently published in Lancet Oncology demonstating the safety and efficacy of
this gene therapy technology in the setting of mismatched donors. A phase III multicentreic trial is
ongoling.
3b4: F Ciceri: Development of new modalities for hematopoietic stem cells transplantation (HSCT)
both in autologous and allogeneic setting to reduce transplant related toxicity. The expertise of the
hSR BMT Unit in allogeneic SCT is already focused in testing new conditioning regimens based on
reduced-toxicity drugs (i.e. treosulfan, clofarabine) and new anti-infective drugs (i.e. posaconazole,
anidulafungin, maribavir) for patients with leukemia, lymphoma, myelosisplasia, myeloma, bone
marrow
failure
syndromes
and
inherited
disorders
such
as
hemoglobinopaties
and
immunodeficiencies. In 2008 the BMT Unit performed 52 allogeneic adult HSCTs, 62 autologus
HSCTs and 17 allogeneic pediatric HSCTs. Our data on clinical performance in 2008 show an
engraftment rate >95% and a treatment related mortality (TRM) of <5% in allogeneic family donor
HSCT and engraftment 100 % and TRM 3 % in autologous HSCT. Several phase II trials with
these drugs are ongoing.
Workpackage 3: Milestones
3a1: Development of a tool to measure outcome in DMD patients undergoing cell therapy studies
and identification of 3 subjects fulfilling the criteria to be enrolled in a phase I trial with
mesoangioblasts.
3a2: Safety of HLA identical donor mesoangioblasts injected intra-muscularly and intra-arterially in
DMD patients.
3a3 Data on mortality, surgical morbidity and diabetes development in patients undergoing
preemptive total pancreatectomy and islet autotransplantation.
3a4 Data on the efficiency of Plerixator to mobilize stem cells in combination with G-CSF.
3b1 Data on the efficacy and safety of autologous fibrin-cultured limbal stem cells transplantation
3b2 Data on safety and efficacy of intra bone infusion of islet grafts in humans.
3b3 Development of new pharmacologic and cellular platforms to allow allogeneic SCT from
alternative donors.
3b4 Development of new modalities for HSCT in autologous and allogeneic setting to reduce
transplant related toxicity.
Deliverables:
Deliverables will be represented by : 1 Publications; 2 Patents ; 3 Protocols
21
Time schedule:
WP n°
0-12 months
12-24 months
24-36 months
1a1 Blasi Ferrari
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1a2 Blasi
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1a3 D’Alessio Blasi
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1a4 Meldolesi
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1a5 Cossu
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1a6 Broccoli
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1a7 Piemonti
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1a8 Naldini Cossu
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1a9 Brunelli
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1b1 Del Maschio
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1b2 Bianchi
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1b3 De Palma
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1b5 Brunelli
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1b6 Cossu
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1b11 Gregori
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1b12 Gregori
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1b13 Roncarolo
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2a1 Brunelli
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2a2 Cossu
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2a3 Clementi
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Broccoli
Naldini
1b4 Manfredi
Rovere
1b7 Clementi E.
1b8 Fleischhauer
1b9 Bacchetta
Roncarolo
Gregori
1b10 Bacchetta
Roncarolo
Gregori
Fleischhauer
Battaglia
22
2a4 Zerbini
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2a5 Peretti
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2b4 Gabellini
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2c3 Politi
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3a1 Cossu Torrente
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Bacchetta
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Guidotti
23
References:
Aiuti et al. Science 28, 5577, 2002.
Barbero A et al. Osteoarthritis Cartilage 12 (6), 476, 2004
Bifari et al. J Cell Mol Med, in press
Brunelli et al. Circ Res, 94: 1571-1578, 2004
Brunelli et al., Proc Natl Acad Sci USA 104, 264, 2007
Chou et al. Cell 135, 449, 2008.
D’Alessio et al. J Cell Sci 121: 3922-3932, 2008.
Dellavalle et al. Nature Cell Bioll. 9, 255, 2007.
Deponti et al. J Cell Biol, 179: 305-319, 2007
Di Terlizzi et al., Biol Blood Marrow Transpl 12: 95-101, 2006
Donisi et al. Cornea. 22:533-8, 2003
Fleischhauer et al., Blood 1072984-2992, 2006:
Gabellini et al. Nature 439, 973, 2006.
Hacein-Bey-Abina et al. J Clin Invest. 118, 3132, 2008.
Hisatsune H et al. Blood 105: 4657-4663, 2005
Hoshiya et al. Mol Ther. 2008 Nov 25. [Epub ahead of print]
Hyun et al. Cell Stem Cell 3, 607, 2008.
Kuroda R et al. Arthritis Rheum 54(2), 433,2006
Mazzi et al. Leukemia 22: 2119-2222, 2008
Meinen et al. J Cell Biol 176, 979, 2007
Melzi, Cell transplantation in press 2009
Miyagoe et al.. FEBS 415, 33, 1997.
Moll et al. Nature 413, 302, 2001.
Murdoch AD et al. Stem Cells 25(11), 2786, 2007
Nisoli et al., Proc Natl Acad Sci USA, 101, 16507, 2004;
Palumbo R. et al J Cell Biol 164: 441-9, 2004
Palumbo R. et al J Cell Biol 179: 33-41, 2007
Pellegrini et al. J Cell Biol. 145:769-82, 1999
Pellegrini et al. J Pathol: 217: 217-28, 2009
Peretti GM et al. Tissue Engineering 12(5), 1151, 2006
Pisconti et al., J Cell Biol 172, 233, 2006;
Qiao et al. PNAS 102, 11999, 2005.
Rama et al. Transplantation. 72:1478-85, 2001
24
Sciorati et al., J Cell Sci 119, 5114, 2006;
Sciorati et al. J Cell Sci, 2009, in press.
Sordi et al. Blood 106, 419-427, 2005
Takahashi et al. Cell 131, 861, 2007.
5. GOVERNANCE
The initial plan is based on monthly meetings consisting of one progress report from one
participating unit and open discussion on progress, funding opportunities and problems. The large
size of the program and the many participants requires the creation of a Steering Committee,
necessary to monitor progress of the program, problems and possible solutions.
25
6. PARTICIPATING UNITS
(COMPONENTS, FUNDING AND PUBLICATIONS 2005-2008)
Francesco Blasi.
Researcher:
Silvia D’Alessio (HSR)
Post-doctoral fellows:
Giorgio Iotti (AIRC), Audrey Laurent (IFOM)
Graduate Students:
Patrizia Marzorati (UVSSR), Silvia Mori (UVSSR), Livia Modica (IFOM), Leila Dardaei (IFOM).
Technicians: Massimo Resnati (HSR), Laura Gerasi (HSR), Ambra Crippa (HSR).
Funding.
AIRC
(2007-2010)
Telethon
(2007-2009)
Cariplo
(2009-2010)
Min San Progetti Finalizzati (2009-2011)
5 relevant publications (2005-2008):
Micali, N. Ferrai, C., Fernandez Diaz, L.C., Blasi, F and Crippa, M.P. Prep1 regulates the intrinsic
apoptotic pathway by directly controlling Bcl-XL expression. In press Mol Cell Biol.
D’Alessio, S., Gerasi, L. and Blasi, F. The urokinase receptor (uPAR) Ko mice keratinocytes fail to
produce EGF-receptor-dependent Laminin-5 affecting migration in vitro and in vivo. 2008. J Cell
Sci 121, 3922-3932.
Caiolfa V, Zamai M, Malengo G, Andolfo A, Madsen CD, Sutin J, Digman M, Gratton E, Blasi F,
Sidenius N. Monomer-dimer dynamics and distribution of GPI-anchored uPAR are determined by
cell surface protein assemblies. (2007) J. Cell Biol., 179, 1067-1082.
Diaz, VM Mori, S, Longobardi, E, Menendez, G., Ferrai, C. RA Keough, A Bachi and F Blasi. p160
myb-binding-protein interacts with Prep1 and inhibits its transcriptional activity. (2007) Mol. Cell
Biol. 27, 7981-7990.
Ferretti, E., J.Carlos Villaescusa, Patrizia Di Rosa, Luis C. Fernandez-Diaz, Elena Longobardi,
Roberta Mazzieri, Annarita Miccio, Nicola Micali, Licia Selleri, Giuliana Ferrari and Francesco
Blasi. Hypomorphic mutation of the TALE gene Prep1 (pKnox1) causes a major reduction of Pbx
Alessandra Biffi (Group Leader)
Capotondo Alessia (PhD student)
Cesani Martina (PhD student)
Delai Stefania (Research Fellow)
Plati Tiziana (Technician)
Funding
Telethon B1 562.000,00 € (2006-2010)
ELA 250.000,00 € (2007-2010)
Italian Ministry of Health 129.800,00 € (with A. Gritti, 2007-2009)
Italian MIUR (PRIN project) 90.000,00 € (2007-2009)
National Tay Sachs and Allied Diseases Association (NTSAD) 22.500,00 € (with A. Gritti, 2009)
1. Visigalli I., Moresco R.M., Belloli S., Politi L.S., Gritti A., Ungaro D., Matarrese M., Turolla
E., Coradeschi E., Falini A., Scotti G., Naldini L., Fazio F., Biffi A.§. Monitoring disease
evolution and treatment response in lysosomal disorders by the peripheral benzodiazepine
receptor ligand PK11195. Neurobiology of Disease, in press.
26
§
2. Biffi A. , Cesani M., Fumagalli F., del Carro U., Baldoli C., Canale S., Gerevini S., Amadio
S., Falautano M., Rovelli A., Comi G., Roncarolo M.G., Sessa M. (2008). Metachromatic
leukodystrophy - mutation analysis provides further evidence of genotype-phenotype
correlation. Clin. Genet. 74: 349-357.
3. Capotondo A., Cesani M., Pepe S., Fasano S., Gregori S., Tononi L., Venneri M.A.,
Brambilla R., Quattrini A., Ballabio A., Cosma M.P., Naldini L., Biffi A.§ (2007). Overexpression of arylsulfatase A in target cells is safe and enables efficacious gene therapy of
metachromatic leukodystrophy. Hum. Gene Ther. 18(9): 821-36.
§
4. Fraldi A.*, Biffi A.* , Lombardi A., Visigalli I., Pepe A., Settembre C., Nusco E., Auricchio
A., Naldini L., Ballabio A., Cosma M.P.§ (2007). SUMF1 enhances sulfatase activities in
vivo in five sulfatase deficiencies. Biochem. J. 403(2): 305-12.
§
5. Biffi A. , Capotondo A., Fasano S., del Carro U., Marchesini S., Azuma H., Malaguti M.C.,
Amadio S., Brambilla R., Grompe M., Bordignon C., Quattrini A., Naldini L.§ (2006). Gene
therapy of metachromatic leukodystrophy reverses neurological damage and deficits in
mice. J. Clin. Invest. 116(11):3070-82. (IF 16,915)
Marco E. Bianchi / Roberta Palumbo
Project Leader :
Roberta Palumbo
Technician:
Francesco De Marchis
Funding;
AIRC
1. Palumbo R, Galvez BG, Pusterla T, De Marchis F, Cossu G, Marcu KB and Bianchi ME (2007)
Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-kB
activation. J Cell Biol 19: 33-40
2. De Mori R, Straino S, Di Carlo A, Pompilio G, Palumbo R, Bianchi ME, Capogrossi MC and
Germani A (2007) Multiple effects of High Mobility Group Box 1 in skeletal muscle regeneration.
Arterioscler Thromb Vasc Biol 27: 2377-83
3. Raucci A, Palumbo R and Bianchi ME (2007) HMGB1: a signal of necrosis. Autoimmunity 40:
285-9
4. Porto A, Palumbo R, Pieroni M, Aprigliano G, Chiesa R, Sanvito F, Maseri A and Bianchi ME
(2006) Smooth muscle cells in human atherosclerotic plaques secrete and proliferate in response
to High Mobility Protein Box 1. FASEB J 20: 2565-6 and E1955-63
5. Limana F, Germani A, Zacheo A, Kajstura J, Di Carlo A, Borsellino G, Leoni O, Palumbo R,
Battistini L, Rastaldo R, Müller S, Pompilio G, Anversa P, Bianchi ME, and Capogrossi MC (2005)
Exogenous High-Mobility Group Box 1 protein induces myocardial regeneration following infarction
via enhanced cardiac c-kit+ cell proliferation and differentiation. Circ Res 97: 73-83
Vania Broccoli:
PhD students:
Serena Giannelli (HSR-ANC); Gaia Colasante (HSR); Alessandro Sessa (HSR)
Sara Ricciardi (HSR-E-RARE)
Fellows:
Federica Ungaro (Telethon), Giorgia Colciago (Telethon), Sara Loponte (AIP)
Funding;
27
Telethon GGP07181
E-RARE
Min San ( Progetti Giovani Ricercatori)
AIP (Associazione Nazionale Parkinson)
Min San Progetti Finalizzati
Associazione Nazionale Cechi
2008-2010
2008-2011
2009-2011
2009-2010
2007-2009
2009-2011
1) Sessa A, Mao CA, Hadjantonakis AK, Klein WH, Broccoli V. (2008). Tbr2 directs conversion of
radial glia into basal precursors and guides neuronal amplification by indirect neurogenesis in the
developing neocortex. Neuron 60(1):56-69.
2) Colasante G, Collombat P, Raimondi V, Bonanomi D, Ferrai C, Maira M, Yoshikawa K,
Mansouri A, Valtorta F, Rubenstein JL, Broccoli V. (2008) Arx is a direct target of Dlx2 and thereby
contributes to the tangential migration of GABAergic interneurons. J Neurosci. 28(42):10674-86.
3) Di Stefano B, Prigione A, Broccoli V. (2008) Efficient genetic reprogramming of unmodified
somatic neural progenitors uncovers the essential requirement of Oct4 and Klf4. Stem Cells Dev.
2008 Aug 25. [Epub ahead of print]
4) Rusconi L, Salvatoni L, Giudici L, Bertani I, Kilstrup-Nielsen C, Broccoli V*, Landsberger N.*
(2008). CDKL5 expression is modulated during neuronal development and its subcellular
distribution is tightly regulated by the C-terminal tail. J Biol Chem. 283(44):30101-11. *Cocorresponding authors
5) Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M,
Isacson O, Jaenisch R. (2008). Neurons derived from reprogrammed fibroblasts functionally
integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proc Natl
Acad Sci U S A. 105(15):5856-61.
Silvia Brunelli:
Thierry Touvier (CAR-MEDEA); Stephanie François (Telethon).
PhD students:
Emanuele Azzoni (Unimib); Patrizia Pessina (Unimib).
Graduate student
Valentina Conti (Telethon)
Funding;
Telethon GGP071013
Cariplo CAR-MEDEA
PI
Cariplo CAR-5121
MinSan PSX56/5/76
PI
Min San Progetti Finalizzati PI
PI
co-PI
2007-2009
2008-2010
2008-2010
2007-2009
2009-2011
Sciorati, C., Touvier, T., Buono, R., Pessina, P., François, S., Perrotta, C., Meneveri, R., Clementi,
E., and Brunelli, S. Necdin is expressed in cachectic skeletal muscle to physiologically
protect fibers from tumor-induced wasting. J Cell Sci, in press, 2009.
Messina, G., Sirabella, D., Monteverde, S., Galvez, B. G., Tonlorenzi, R., Schnapp, E., De Angelis,
L., Brunelli, S., Relaix, F., Buckingham, M., and Cossu, G. Skeletal Muscle Differentiation
Of Embryonic Mesoangioblasts Requires Pax3 Activity. Stem Cells, 2008
Deponti, D., Francois, S., Baesso, S., Sciorati, C., Innocenzi, A., Broccoli, V., Muscatelli, F.,
Meneveri, R., Clementi, E., Cossu, G., and Brunelli, S. Necdin mediates skeletal muscle
regeneration by promoting myoblast survival and differentiation. J Cell Biol, 179: 305-319,
2007.
Brunelli, S., Sciorati, C., D'Antona, G., Innocenzi, A., Covarello, D., Galvez, B. G., Perrotta, C.,
Monopoli, A., Sanvito, F., Bottinelli, R., Ongini, E., Cossu, G., and Clementi, E. Nitric oxide
28
release combined with nonsteroidal antiinflammatory activity prevents muscular dystrophy
pathology and enhances stem cell therapy. Proc Natl Acad Sci U S A, 104: 264-269, 2007
Brunelli, S., Relaix, F., Baesso, S., Buckingham, M., and Cossu, G. Beta catenin-independent
activation of MyoD in presomitic mesoderm requires PKC and depends on Pax3
transcriptional activity. Dev Biol, 304: 604-614, 2007.
Emilio Clementi:
Researchers:
Clara De Palma
(Unimi-Sacco)
Cristiana Perrotta (Unimi-Sacco)
Viviana Pisa (Telethon); Chris Panzeri (Cariplo)
Graduate students:
Roberta Buono (Unimi); Denise Cazzato (Medea); Laura Bizzozero (Uimi), Serena Pisoni (Medea)
Technicians:
Clara Sciorati (HSR); Greta Milani (EC)
Funding;
EC Otpistem (FP7 Project 223098)
Telethon GGP07006
AIRC 5469
AFM 13470
2009-2013
2008-2010
2009-2011
2008-2009
2008-2009
1) E. Nisoli, C. Tonello, A. Cardile, V. Cozzi, R. Bracale, L. Tedesco, S. Falcone, A. Valerio, O.
Cantoni, E. Clementi, S. Moncada and M.O. Carruba. Calorie restriction promotes mitochondrial
biogenesis by inducing expression of eNOS. Science, 310: 314-317, 2005.
2) A. Pisconti, S. Brunelli, M. Di Padova, C. De Palma, D. Deponti, S. Baesso, V. Sartorelli, G.
Cossu, and E. Clementi. Follistatin induction by nitric oxide through cyclic GMP: a tightly regulated
signalling pathway that controls myoblast fusion. J. Cell Biol. 172: 233-244, 2006
3) C. Sciorati, B.G. Galvez, S. Brunelli, E. Tagliafico, S. Ferrari, G. Cossu, and E. Clementi. Ex vivo
treatment with nitric oxide increases mesoangioblast therapeutic efficacy in muscular dystrophy. J.
Cell Sci. 119: 5114-5123, 2006
4) S. Brunelli, C. Sciorati, G. D’Antona, A. Innocenzi, D. Covarello, B.G. Galvez, C. Perrotta, A.
Monopoli, F. Sanvito, R. Bottinelli, E. Ongini, G. Cossu, and E. Clementi. NO release combined
with nonsteroidal antinflammatory activity prevents muscular dystrophy pathology and enhances
stem cell therapy. Proc. Natl. Acad. Sci. USA 104: 264-269, 2007
5) C. Colussi, C. Mozzeta, A. Gurtner, B. Illi, J. Rossi, S. Straino, G. Ragone, M. Pescatori, G.
Zaccagnini, A. Antonini, G. Minetti, F. Martelli, G. Piaggio, P. Gallinari, C. Steinkluher, E. Clementi,
C. Dell’Aversana, L. Altucci, A. Mai, M.C. Capogrossi, P.L. Puri, and C. Gaetano. HDAC2 blockade
by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular
dystrophy treatment. Proc. Natl. Acad. Sci. USA 105: 19183-19187, 2008
Giulio Cossu:
Researchers:
Messina Graziella (Unimi)
Dellavalle Arianna (FIRB); Hoshiya Hidetoshi (ERC); Ugarte Gonzalo (EC)
Graduate students:
Benedetti Sara (Uniroma1); Cappellari Ornella (Uniroma1); Tedesco Saverio (HSR)
Maciotta Simona (HSR)
29
Technicians:
Covarello Diego (EC); Innocenzi Anna (HSR); Monteverde Stefania (EC); Perani Laura (AFM);
Tonlorenzi Rossana (HSR)
Funding;
EC Otpistem (FP7 Project 223098)
EC Heart Repair (LSHM-CT-2005-0186309)
EC MyoAmp (LSH-2005-1.2.4-7)
ERC 2008 AdG 233263
Telethon GGP03080
FIRB RBIN063EWP
Cure Duchenne
AFM 12071
2009-2013
2007-2009
2007-2009
2009-2012
2008-2010
2008-2011
2008
2008-2009
2008-2009
1) Galvez, B.G., Sampaolesi, M., Brunelli, S., Covarello, D., Gavina, M., Rossi, B., Costantin, G.,
Torrente, Y. and Cossu (2006). Complete repair of dystrophic skeletal muscle by mesoangioblasts
with enhanced migratory ability. J. Cell Biol. 174, 231-243.
2) Sampaolesi, M., Blot, S., D’Antona, G., Granger, N., Tonlorenzi, R., Innocenzi, A., Mognol, P.,
Thibaud, J.L., Galvez, B.G., Barthélémy, I., Perani, L., Mantero, S., Guttinger, M., Pansarasa, O.,
Rinaldi, C., Cusella De Angelis, M.G., Torrente, Y., Bordignon, C., Bottinelli, R. and Cossu, G.
(2006). Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature 444:5749.
3) Morosetti, R., Mirabella, M. Gliubizzi, C., Broccolini, A., De Angelis, L., Tagliafico, E.,
Sampaolesi, M., Gidaro, T., Papacci, M., Roncaglia, E., Rutella, S., Ferrari, St., Tonali, P.A., Ricci,
E. and Cossu, G. (2006). MyoD expression reverts a BHLHB3-dependent block of myogenic
differentiation of human mesoangioblasts from inclusion-body myositis muscle (2006). Proc. Natl.
Acad. Sci. USA 103:16995-7000.
4) Dellavalle, A, Sampaolesi, M, Tonlorenzi, R, Tagliafico, E, Sacchetti, B, Perani, L,, Innocenzi,
B, Galvez, BG, Messina, G, Morosetti, R, Li, S, Belicchi, M, Peretti, G, Chamberlain, JS,
Wright, WE, Torrente, Y, Ferrari, S, Bianco, P and Cossu, G. 2007. Pericytes of human skeletal
muscle are myogenic precursors distinct from satellite cells. Nature Cell Biol. 9:255-267.
5) Gargioli, C., Coletta, M., De Grandis, F., Cannata, S.M. and Cossu G. 2008. PlGF-MMP9
expressing cells restore microcirculation and efficacy of cell therapy in old dystrophic muscle.
Nature Med. 14:973-8.
Alessandro Del Maschio:
Project Leader :
Francesco De Cobelli, MD
Researchers:
Antonio Esposito, MD
Claudio Losio, MD
Massimo Venturini, MD
Funding;
AIRC (with F. Blasi)
CARIPLO (with R. Pardi)
1) Manfredi AA, Capobianco A, Esposito A, De Cobelli F, Canu T, Monno A, Raucci A, Sanvito F,
Doglioni C, Nawroth PP, Bierhaus A, Bianchi ME, Rovere-Querini P, Del Maschio A. Maturing
30
dendritic cells depend on RAGE for in vivo homing to lymph nodes. J Immunol. 2008 Feb
15;180(4):2270-5.
Michele De Palma/Luigi Naldini:
Director: Luigi Naldini, MD, PhD
Project Leader: Michele De Palma, PhD
Senior post-doc: Roberta Mazzieri, PhD
Post-doc: Mary Anna Venneri, PhD
PhD students: Ferdinando Pucci; Erika Zonari, Mario Squadrito
Fellow: Daniela Biziato
Technician: Davide Moi
Funding;
AIRC 2008-2010
EU (FP6 Tumor-Host Genomics) 2007-2009
Ministry of Health (Challenge in Oncology) 2008-2010
1) De Palma M, R Mazzieri, LS Politi, F Pucci, E Zonari, S Mazzoleni, G Sitia, D Moi, MA Venneri,
S Indraccolo, A Falini, LG Guidotti, R Galli, L Naldini. Tumor-targeted Interferon-α Delivery by
Tie2-Expressing Monocytes Inhibits Tumor Growth and Metastasis.
Cancer Cell, 2008 Oct 7;14(4):299-311.
2) De Palma M, C Murdoch, MA Venneri, L Naldini, CE Lewis. Tie2-expressing Monocytes:
Regulation of Tumor Angiogenesis and Therapeutic Implications.
Trends Immunol. 2007 Dec;28(12):519-24.
3) Venneri MA, M De Palma, M Ponzoni, F Pucci, C Scielzo, E Zonari, R Mazzieri, C Doglioni, L
Naldini. Identification of Proangiogenic Tie2-Expressing Monocytes (TEMs) in Human Peripheral
Blood and Cancer.
Blood. 2007 Jun 15;109(12):5276-85.
4) De Palma M, L Naldini. Role of Haematopoietic Cells and Endothelial Progenitors in Tumour
Angiogenesis.
Biochim Biophys Acta–Reviews on Cancer, 2006 Aug;1766(1):159-66.
5) De Palma M, MA Venneri, R Galli, L Sergi Sergi, LS Politi, M Sampaolesi, L Naldini. Tie2
Identifies a Hematopoietic Lineage of Pro-Angiogenic Monocytes Required for Tumor Vessel
Formation and a Mesenchymal Population of Pericyte Progenitors.
Cancer Cell. 2005 Sep; 8(3):211-26.
Heads: Angelo Manfredi / Patrizia Rovere-Querini
Researchers:
Corna Gianfranca
Maugeri Norma
PhD students:
Bosurgi Lidia
Campana Lara
Castiglioni Alessandra
Cottone Lucia
Vezzoli Michela
31
Technicians:
Capobianco Annalisa
Monno Antonella
Fundings:
FIRB IDEAS
(FIRBROVERE)
Metadistretti
Ricerca Oncologica (ROCONV20/07)
AIRC
(R0354)
PRIN
(R0331)
Strategico Oncologia (RO-7OAF5-1)
Ricerca Finalizzata (RF07-MDM-1)
2009-2014
2009-2012
2007-2010
2009-2010
2007-2009
2008-2011
2008-2010
Manfredi Angelo
1. Maugeri N, Rovere-Querini P, Evangelista V, Covino C, Capobianco A, Bertilaccio MT,
Piccoli A, Totani L, Cianflone D, Maseri A, Manfredi AA. Neutrophils phagocytose
activated platelets in vivo: a phosphatidylserine, P-selectin and ß2 integrin-dependent cell
clearance program. Blood. 2009 In press.
2. Bianchi ME, Manfredi AA. Immunology. Dangers in and out. Science. 2009; 323:1683-4.
3. Manfredi AA, Capobianco A, Esposito A, De Cobelli F, Canu T, Monno A, Raucci A,
Sanvito F, Doglioni C, Nawroth PP, Bierhaus A, Bianchi ME, Rovere-Querini P, Del
Maschio A. Maturing dendritic cells depend on RAGE for in vivo homing to lymph nodes. J
Immunol. 2008; 180:2270-5.
4. Manfredi AA, Rovere-Querini P, Bottazzi B, Garlanda C, Mantovani A. Pentraxins, humoral
innate immunity and tissue injury. Curr Opin Immunol. 2008; 20:538-44.
5. Baruah P, Propato A, Dumitriu IE, Rovere-Querini P, Russo V, Fontana R, Accapezzato D,
Peri G, Mantovani A, Barnaba V, Manfredi AA. The pattern recognition receptor PTX3 is
recruited at the synapse between dying and dendritic cells, and edits the cross-presentation
of self, viral, and tumor antigens. Blood. 2006; 107:151-8.
Rovere-Querini Patrizia
1. Lolmede K, Campana L, Vezzoli M, Bosurgi L, Tonlorenzi R, Clementi E, Bianchi ME,
Cossu G, Manfredi AA, Brunelli S, Rovere-Querini P. Inflammatory and alternatively
activated human macrophages attract vessel-associated stem cells, relying on separate
HMGB1- and MMP-9-dependent pathways. J Leukoc Biol. 2009; In press.
2. Campana L, Bosurgi L, Rovere-Querini P. HMGB1: a two-headed signal regulating tumor
progression and immunity. Curr Opin Immunol. 2008; 20:518-23.
3. Urbonaviciute V, Fürnrohr BG, Meister S, Munoz L, Heyder P, De Marchis F, Bianchi ME,
Kirschning C, Wagner H, Manfredi AA, Kalden JR, Schett G, Rovere-Querini P, Herrmann
M, Voll RE. Induction of inflammatory and immune responses by HMGB1-nucleosome
complexes: implications for the pathogenesis of SLE. J Exp Med. 2008; 205:3007-18.
4. Rovere-Querini P, Antonacci S, Dell'Antonio G, Angeli A, Almirante G, Cin ED, Valsecchi
L, Lanzani C, Sabbadini MG, Doglioni C, Manfredi AA, Castiglioni MT. Plasma and tissue
expression of the long pentraxin 3 during normal pregnancy and preeclampsia. Obstet
Gynecol. 2006; 108:148-55.
5. Dumitriu IE, Baruah P, Valentinis B, Voll RE, Herrmann M, Nawroth PP, Arnold B, Bianchi
ME, Manfredi AA, Rovere-Querini P. Release of high mobility group box 1 by dendritic
cells controls T cell activation via the receptor for advanced glycation end products. J
Immunol. 2005; 174:7506-15.
Katharina Fleischhauer:
32
Researchers:
Jessica Marcon (AIRC)
Graduate students:
Luca Vago (HSR), Pietro Crivello (Cariplo)
Technicians:
Laura Zito (Ministry of Health)
Funding;
AIRC IG 44/2007
Cariplo 2007.5486
Ministero della Salute Challenge in Oncology RO10/07R
Telethon GGP08201
Ministero della Salute Ricerca Finalizzata 2007
2008-2011
2008-2010
2008-2011
2009-2011
2009-2011
1. Vago L, Forno B, Sormani MP, Crocchiolo R, Zino E, Di Terlizzi S, Lupo Stanghellini MT,
Mazzi B, Perna SK, Bondanza A, Middleton D, Palini A, Bernardi M, Bacchetta R, Peccatori
J, Rossini S, Roncarolo MG, Bordignon C, Bonini C, Ciceri F, Fleischhauer K. Temporal,
quantitative and functional characteristics of single-KIR positive alloreactive NK cell
recovery account for impaired graft versus leukemia activity after haploidentical HSCT.
Blood 2008: 112: 3488-3499. Epub 2008 Jul 21.
2. Mazzi B, Clerici TD, Zanussi M, Lupo Stanghellini MT, Vago L, Sironi E, Peccatori J,
Bernardi M, Carrera P, Palini A, Rossini S, Bordigon C, Bonini C, Ferrari M, Ciceri F,
Fleischhauer K. Genomic typing for patient-specific human leukocyte antigen-alleles is an
efficient tool for relapse detection of high-risk hematopoietic malignancies after stem cell
transplantation from alternative donors. Leukemia 2008: 22: 2119-2222. Epub May 1.
3. Zino E, Vago L, Di Terlizzi S, Mazzi B, Zito L, Sironi E, Rossini S, Bonini C, Ciceri F,
Roncarolo MG, Bordignon C, Fleischhauer K. Frequency and targeted detection of HLADPB1 T cell epitope disparities relevant in unrelated hematopoietic stem cell
transplantation. Biol Blood Marrow Transplant 2007: 13: 1031-1040.
4. Di Terlizzi S, Zino E, Mazzi B, Magnani C, Tresoldi C, Perna SK, Bregni M, Rossini S,
Ciceri F, Bordignon C, Bonini C, Fleischhauer K. Therapeutic and diagnostic applications
of minor histocompatibility antigen HA-1 and HA-2 disparities in allogeneic hematopoietic
stem cell transplantation: a survey of different populations. Biol Blood Marrow Transplant
2006: 12: 95-101.
5. Fleischhauer K, Locatelli F, Zecca M, Orofino MG, Giardini C, De Stefano P, Pession A,
Iannone AM, Carcassi C, Zino E, La Nasa G. Graft rejection after unrelated donor
hematopoietic stem cell transplantation for thalassemia is associated with non-permissive
HLA-DPB1 disparity in host-versus-graft direction. Blood 2006: 107: 2984-2992. Epub 2005
Nov 29.
Davide Gabellini:
Sergia Bortolanza (ERC); Cristina Godio (ERC); Alexandros Xynos (MDA); Mariaelena Pistoni
(ERC)
Graduate students:
Daphne Cabianca (UniSR); Claudia Huichalaf (UniSR)
Funding
DTI
EC EURASNET NoE
AFM
ERC StG
2006-2011
2006-2009
2007-2009
2008-2013
33
MDA
2009-2011
Gabellini D, D’Antona G, Moggio M, Prelle A, Zecca C, Adami R, Angeletti B, Ciscato P, Pellegrino
MA, Bottinelli R, Green MR, Tupler R. 2006. Facioscapulohumeral Muscular Dystrophy in
Transgenic Mice by Over-Expression of FRG1. Nature 439:973-977.
Rossella Galli
Researchers:
Rossella Galli (HSR)
Barbara Cipelletti (Fondazione Cariplo); Mauro Pala (Fondazione Cariplo).
Graduate students:
Stefania Mazzoleni (Ministero della Salute, Programma Integrato Oncologia); Daniela Corno
(UniSR-Molecular Medicine); Laura Magri (UniSR-Molecular and Cellular Biology).
Technicians:
Vivian Deidda Vigoriti (Compagnia San Paolo).
Funding:
Ministero della Salute, Programma Integrato Oncologia
Compagnia di San Paolo
Fondazione Cariplo
Istituto Superiore Sanità – Alleanza contro il cancro
2008-2011
2007-2010
2008-2010
2007-2009
1. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, DiMeco F
and Vescovi A (2004). Isolation and characterization of tumorigenic, stem-like neural
precursors from human glioblastoma. Cancer Research, 64: 7011-7021.
2. Colombo, E. Giannelli, S. G., Galli, R., Tagliafico, E., Foroni, C., Tenedini, E., Ferrari, S.,
Corte, G., Vescovi, A., Cossu, G., Broccoli, V. (2006). Embryonic stem-derived versus
somatic neural stem cells: a comparative analysis of their developmental potential and
molecular phenotype. Stem Cells, 24: 825-34.
3. De Palma M, Venneri MA, Galli R, Sergi LS, Politi LS, Sampaolesi M, Naldini L. (2005).
Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor
vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell
8:211-226.
4. Vescovi A, Galli R, and Reynolds B (2006). Brain tumour stem cells. Nature Reviews
Cancer, 6: 425-436.
5. Foroni C., Galli R, Cipelletti B, Caumo A, Alberti S, Fiocco R, Vescovi A (2007). Resilience
To Transformation And Inherent Genetic And Functional Stability of Adult Neural Stem
Cells Ex Vivo. Cancer Research, 67(8): 3725-33.
6. De Palma M, Mazzieri R, Politi LS, Pucci F, Zonari E, Sitia G, Mazzoleni S, Moi D, Venneri
MA, Indraccolo S, Falini A, Guidotti LG, Galli R, Naldini L (2008). Tumor-targeted
interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and
metastasis. Cancer Cell, 14(4):299-311.
A. Gritti
34
PhD students:
Santambrogio Sara (UniHSR); Cavazzin Chiara (Univ Perugia); Neri Margherita (HSR), Lattanzi
Annalisa (Univ Perugia)
Fellows
Alcala’-Franco Beatriz (HSR)
Technicians:
Maderna Claudio
1. Martino S, di Girolamo I, Cavazzin C, Tiribuzi R, Galli R, Rivaroli A, Valsecchi M, Sandhoff
K, Sonnino S, Vescovi A, Gritti A* and Orlacchio A*. Neural precursor cell cultures from
GM2-gangliosidosis animal models recapitulate the biochemical and molecular hallmarks
of the brain pathology. J. of Neurochemistry, in press. * corresponding authors
2. Martino S, Tiribuzi R, Tortori A, Conti D, Visigalli I, Lattanzi A, Biffi A, Gritti A and Orlacchio
A. Specific determination of β-galactocerebrosidase activity via competitive inhibition of βgalactosidase. Clinical Chemistry, in press
3. Santoni de Sio FR, Gritti A, Cascio P, Neri M, Sampaolesi M, Galli C, Luban J, Naldini L.
Lentiviral Vector Gene Transfer is Limited by the Proteasome at Post-Entry Steps in
Various Types of Stem Cells. Stem Cells. 2008 26(8):2142-52. Epub 2008 May 15.
4. Neri M, Maderna C, Cavazzin C, Deidda-Vigoriti V, Politi LS, Scotti G, Marzola P, Sbarbati
A, Vescovi AL, Gritti A. Efficient In Vitro Labeling Of Human Neural Precursor Cells With
Superparamagnetic Iron Oxide Particles: Relevance For In Vivo Cell Tracking. Stem
Cells. 2008 26(2):505-16. Epub 2007 Nov 1.
5. Cavazzin C, Ferrari D, Facchetti F, Russignan A, Vescovi AL, La Porta CA, Gritti A.
Unique expression and localization of aquaporin- 4 and aquaporin-9 in murine and human
neural stem cells and in their glial progeny. Glia. 2006 15;53(2):167-81.
FUNDING
Telethon TGT06B02
NTSAD
Italian Ministry of Health (ex-art 56L289/2002)
European Leukodystrophy Association (ELA)
2006-2010
31/08/2008-31/08/2009
2007-2009
2009-2010
Jacopo Meldolesi
Researcher:
Paola Podini (HSR)
Senior Post-doc:
Rosalba D’Alessandro (Uni-SR)
PhD students:
Ilaria Prada (Uni-SR)
Technician:
Gabriella Racchetti (HSR)
Funding;
IIT
MIUR prot. RBLA03AF28
MIUR prot. 2006059395
2007-2011
2007-2009
2007-2009
PI
PI
PI
35
1. D’Alessandro R, Klajn A and Meldolesi J. Expression of dense-core vesicles and of their
exocytosis are governed by the repressive transcription factor, NRSF/REST. Ann N Y Acad
Sci, in press
2. D’Alessandro R, Klajn A, Stucchi L, Podini P, Malosio ML and Meldolesi J. Expression of
the neurosecretory process in PC12 cells is governed by REST. J Neurochem
2008;105:1369-138
3. Volterra A and Meldolesi J. Astrocytes, from brain glue to communication elements: the
revolution. Nat Rev Neurosci 2005;6:626-640
4. Sala C, Roussignol G, Meldolesi J and Fagni L. Key role of the postsynaptic density
scaffold proteins Shank and Homer in the functional architecture of Ca2+ homeostasis at
dendritic spines in hippocampal neurons. J Neurosci 2005; 25:4587-4592
5. Malosio ML, Giordano T, Laslop A and Meldolesi J. Dense-Core Granules: a Specific
Hallmark of the Neuronal/Neurosecretory cell Phenotype. J Cell Science 2004; 117:743749
6. Grundschober C, Malosio ML, Astolfi L, Giordano T, Nef P. and Meldolesi J.
Neurosecretion competence. A comprehensive gene expression program identified in PC12
cells. Biol Chem 2002; 277:36715-24
GIUSEPPE PERETTI:
Deponti Daniela (UNIMI)
Residents and applicants to a residency program
Laura Mangiavini (UNIMIB)
Celeste Scotti (UNIMI)
Alessandro Pozzi
Rosa Ballis
Attending
Gianfranco Fraschini (HSR)
Corrado Sosio (HSR)
Funding;
BAYER (ODIX aHip-OD study)
BAYER (RECORD I study)
FIRST (UNIMI)
CARIPLO FOUNDATION
2005
2006
2007
2008-2010
1) Peretti G.M., Xu J.W., Bonassar L.J., Kirchhoff K.H., Yaremchuk M.J., Randolph M.A. 2006.
Review of injectable cartilage engineering using fibrin gel in mice and swine models. Tissue
Engineering May;12(5):1151-68.
2) Dellavalle, A, Sampaolesi, M, Tonlorenzi, R, Tagliafico, E, Sacchetti, B, Perani, L,, Innocenzi, B,
Galvez, BG, Messina, G, Morosetti, R, Li, S, Belicchi, M, Peretti, G, Chamberlain, JS, Wright, WE,
Torrente, Y, Ferrari, S, Bianco, P and Cossu, G. 2007. Pericytes of human skeletal muscle are
myogenic precursors distinct from satellite cells. Nature Cell Biol. 9:255-267.
3) Scotti C., Buragas M.S., Mangiavini L., Sosio C., Di Giancamillo A., Domeneghini C., Fraschini
G., Peretti G.M. 2007. A tissue engineered osteochondral plug: an in vitro morphological
evaluation. Knee Surg Sports Traumatol Arthrosc Nov;15(11):1363-9.
36
4) Sosio C., Boschetti F., Bevilacqua C.. Mangiavini L., Scotti C., Buragas M.S., Biressi S., Gigante
A., Fraschini G., Peretti G.M. 2007. Effect of blood on the morphological, biochemical, and
biomechanical properties of engineered cartilage. Knee Surg Sports Traumatol Arthrosc 2007
Oct;15(10):1251-7.
5) Boschetti F., Peretti G.M. 2008. Tensile and compressive properties of healthy and osteoarthritic
human articular cartilage. Biorheology. 45(3-4):337-44.
Lorenzo Piemonti:
ISLET PROCESSING FACILITY
Researcher:
Rita Nano (HSR)
Technicians:
Raffaella Melzi (HSR); Antonioli Barbara (HSR)
BETA CELL BIOLOGY UNIT
Post doctoral fellow:
Leda Racanicchi (HSR)
PhD student:
Valeria Sordi (Uni Vita Salute San Raffaele)
Fellows:
Alessia Mercalli (HSR); Dugnani Erica (HSR); Cantarelli Elisa (HSR)
Funding;
-Diabetes Type 1 Prediction, Early Pathogenesis and Prevention EC
2008-11
-Protection of graft failure of transplanted pancreatic islets in T1D Dompe
2008-09
-New targets in tumor microenvironment
Min Sal
2008-10
-Identification of novel genetic pathways regulating the
Cariplo 2008-10
development and biological behaviour of cancer stem cells
-Multi step trial towards single donor islet transplantation in T1D JDRF-ECIT 2007-9
patients using calcineurin inhibitor free immunosuppression
-Islet for basic research program
JDRF-ECIT 2009
1) Sordi V, Melzi R, Mercalli A, Formicola R, Doglioni C, Ferrari G, Antonioli B, Nano R, Bonifacio
E, Piemonti L Mesenchymal cells appearing in pancreatic tissue culture are bone marrow-derived
stem cells with the capacity to improve transplanted islet function (submitted)
2) Melzi R, Sanvito F, Mercalli A, Andralojc K, Bonifacio E and Piemonti L. Intrahepatic islet
transplant in the mouse: functional and morphological characterization. Cell transplantation: in
press
3) Marchesi F§, Piemonti L§, Fedele G, Destro A, Roncalli M, Albarello L, Doglioni C, Anselmo A,
Doni A, Bianchi P, Laghi L, Malesci A, Cervo L, Malosio ML, Reni M, Zerbi A, Di Carlo V,
Mantovani A, Allavena P. The chemokine receptor CX3CR1 is involved in the neural tropism and
malignant behavior of pancreatic ductal adenocarcinoma. Cancer Res. 2008 Nov 1;68(21):9060-9.
(§ these authors equally contributed to the study)
4) Melzi R, Battaglia M, Draghici E, Bonifacio E, Piemonti L. Relevance of hyperglycemia on the
timing of functional loss of allogeneic islet transplants: implication for mouse model.
Transplantation. 2007 Jan 27;83(2):167-73
5) Sordi V, Malosio ML, Marchesi F, Mercalli A, Giordano T, Belmonte N, Ferrari G, Leone BE,
Bertuzzi F, Zerbini G, Allavena P, Bonifacio E and Piemonti L. Bone marrow mesenchymal stem
cells express a restricted set of functionally active chemokine receptors capable of promoting
migration to pancreatic islets. Blood. 2005;106:419-27. Epub 2005 Mar 22.
37
Letterio Politi (Group Leader, Neuroradiology Research Group)
Antonella Iadanza (Technician)
Sara Pizzi (Research Fellow)
Funding;
CARIPLO € 250.000,00 (2006-2009)
CARIPLO € 90.000,00 (2008-2011)
1) Politi LS. “MR-based Imaging of neural stem cells”. Review. Neuroradiology, 2007;6: 523-534.
Epub 2007 March 8.
2) Politi LS, Bacigaluppi M, Brambilla E, Cadioli M, Falini A, Comi G, Scotti G, Martino G, Pluchino
S. “Magnetic Resonance-based Tracking and Quantification of Intravenously-injected Neural Stem
Cell Accumulation in the Brain of Mice With Experimental Multiple Sclerosis”. Stem Cells 2007;
25(10):2583-92. Epub 2007 Jun 28.
3) Neri M, Maderna C, Cavazzin C, Deidda-Vigoriti V, Politi LS, Scotti G, Marzola P, Sbarbati A,
Vescovi AL, Gritti A. “Efficient in vitro labeling of human neural precursor cells with
superparamagnetic iron oxide particles: relevance for in vivo cell tracking.”. Stem Cells 2008;
26(2):505-16. Epub 2007 Nov 1.
4) De Palma M, Mazzieri R, Politi LS, Pucci F, Zonari E, Sitia G, Mazzoleni S, Moi D, Venneri MA,
Indraccolo S, Falini A, Guidotti LG, Galli R, Naldini L. “Tumor-targeted interferon-alpha delivery by
Tie2-expressing monocytes inhibits tumor growth and metastasis”. Cancer Cell 2008; 14:299-311.
5) De Palma M, Venneri MA, Galli R, Sergi LS, Politi LS, Sampaolesi M, Naldini L. “Tie2 identifies
a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a
mesenchymal population of pericyte progenitors”. Cancer Cell 2005; 8:211-226.
Previtali Stefano Carlo
Scarlato Marina, MD researcher
Teuta Domi, PhD, post-doc
Porrello Emanuela, PhD student
Lorenzetti Isabella, Technician
Lopez Ignazio, Specializzando
Funding
Telethon GGP08037 2009-2011
5 relevant publication 2005-2008
1) Nodari A, Previtali SC, Dati G, Occhi S, Court FA, Colombelli A, Zambroni D, Dina G, Del Carro
U, Campbell KP, Quattrini A, Wrabetz L, Feltri ML. α6β4 integrin and dystroglycan cooperate to
stabilize the myelin sheath. J Neurosci 2008; 28: 6714-6719.
2) Previtali SC, Malaguti MC, Riva N, Scarlato M, Dacci P, Dina G, Triolo D, Porrello E, Fazio R,
Comi G, Bolino A, Quattrini A. The extracellular matrix composition affects regeneration and
clinical outcome in axonal neuropathies. Neurology 2008, 71(5): 322-331
3) Benedetti S, Menditto I, Degano M, Rodolico C, Merlini L, D'Amico A, Palmucci L, Berardinelli A,
Pegoraro E, Trevisan CP, Morandi L, Moroni I, Galluzzi G, Bertini E, Toscano A, Olivè M, Bonne G,
Mari F, Caldara R, Fazio R, Mamm I, Carrera P, Toniolo D, Comi G, Quattrini A, Ferrari M, and
Previtali SC. Phenotypic clustering of lamin A/C mutations in neuromuscular patients. Neurology
2007; 69(12): 1285-1292
4) Triolo D, Dina G, Lorenzetti I, Malaguti MC, Morana P, Del Carro U, Comi G, Messing A,
Quattrini A, Previtali SC. Loss of Glial Fibrillary Acidic Protein (GFAP) impairs Schwann cell
proliferation and delays nerve regeneration after damage. J Cell Sci 2006; 119: 3981-3993
38
5) Benedetti S, Bertini E, Iannaccone S, Angelini C, Toniolo D, Sferrazza B, Carrera P, Comi G,
Ferrari M, Quattrini A, Previtali SC. Dominant LMNA mutations can cause combined muscular
dystrophy and peripheral neuropathy. J Neurol Neurosurg Psy 2005; 76: 1019-1021
Maria Grazia Roncarolo:
Researchers:
Bacchetta Rosa (HSR), Battaglia Manuela (HSR), Gregori Silvia (HSR)
Graduate students:
Passerini Laura (HSR), Sara Di Nunzio (Universita’ di Tor Vergata), Chiara Francesca Magnani
(HSR), Maura Rossetti (HSR), Giada Alberigo (HSR), Didem Aydin (HSR).
MD PhD student.
Lucarelli Barbarella (Visiting scientist)
Technicians:
Grazia Andolfi (HSR), Claudia Sartirana (HSR), Daniela Tomasoni (HSR), Eleonora Tresoldi (HSR)
Funding;
RISET (FP6 Project)
Telethon A3 project
Telethon E1 project
Telethon E2 project
Telethon GGP07241
Cariplo Nobel
Cariplo
AIRC 2007
Min Progetto giovani ricercatori
2005-2010
2006-2010
2006-2010
2006-2010
2008-2010
2007-2009
june2008-june2010
2007-2009
2008-2010
1) S. Gregori, R. Bacchetta, E. Hauben, M. Battaglia and M.G. Roncarolo (2005). Regulatory T
cells: prospective for clinical application in hematopoietic stem cell transplantation. Curr Opin
Hematol 12: 451-456.
2) R. Bacchetta, L. Passerini, E.Gambineri, M. Dai, S.E.Allan, L. Perroni, F. Dagna-Bricarelli, C.
Sartirana, S. Matthes-Martin, A. Lawitschka, C. Azzari, S.F. Ziegler, M.K. Levings, and M.G.
Roncarolo. (2006). Defective regulatory and effector T cell functions in patients with FOXP3
mutations. J Clin. Invest. 116:1713-1722.
3) M.G. Roncarolo, S. Gregori, M. Battaglia, R. Bacchetta, K. Fleischhauer and M.K. Levings.
(2006). Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol
Reviews. 212:28-50.
4) 24. M. Battaglia, A. Stabilini, B. Migliavacca, J. Horejs-Hoeck, T. Kaupper, and M.G. Roncarolo.
(2006). Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of
both healthy subjects and Type 1 diabetic patients. J Immunol. 177: 8338-8347.
5) M.G. Roncarolo, and M. Battaglia (2007). Regulatory T-cell immunotherapy for tolerance to self
antigens and alloantigens in humans. Nat Rev Immunol 7:585-598.
Gianpaolo Zerbini (Diabetic Complications Unit)
Gemma Tremolada (HSR), Anna Maestroni (HSR)
Graduate students:
Anna Pulcina (UniSR)
Technicians:
Daniela Gabellini (HSR)
Funding;
JDRF
Associazione Nazionale Cechi
2007-2010
2009-2010
39
1. Asnaghi V, Lattanzio R, Mazzolari G, Pastore MR, Ramoni A, Maestroni A, Ruggieri D, Luzi L,
Brancato R, Zerbini G. Increased clonogenic potential of circulating endothelial progenitor cells
(EPCs) in patients with type 1 diabetes and proliferative retinopathy. Diabetologia. 49:1109-1111,
2006
2. Del Bo R, Scarlato M, Ghezzi S, Maestroni A, Sjölind L, Forsblom C, Wessman M, Groop P-H,
Comi GP, Bresolin N, Luzi L, Zerbini G. VEGF gene variability and type 1 diabetes: evidence for a
protective role. Immunogenetics 58:107-112, 2006
3. Zerbini G , Piemonti L, Maestroni A, Dell’Antonio G, Bianchi G. Stem cells and the kidney, a new
therapeutic tool? J Am Soc Nephrol 2006 17:S123-6
4. Zerbini G, Bonfanti R, Meschi F, Bognetti E, Paesano PL, Gianolli L, Querques M, Maestroni A,
Calori G, Del Maschio A, Fazio F, Luzi L, Chiumello G. Persistent renal hypertrophy and faster
decline of glomerular filtration rate precede the development of microalbuminuria in type 1
diabetes. Diabetes 2006; 55:2620-2625.
5. Tumor angiogenesis. Zerbini G, Lorenzi M, Palini A. N Engl J Med. 2008 14; 359:763;
40

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