Recent Advances in Angiogenesis and ... - Bentham Science

22 Recent Advances in Angiogenesis and Antiangiogenesis, 2009 Raffaghello and Pistoia
rationale for the use of allogeneic MSC to treat
severe graft-versus-host disease (GvHD) and,
possibly, autoimmune disorders [27-29]. In this
connection, encouraging results have been obtained
in patients with GvHD, in which the effect mediated
by MSC was probably due to the inhibition of donor
T-cell reactivity to histocompatibility antigens of the
normal tissues of the recipient [30].
On the other hand, MSC have been used to treat
children with severe osteogenesis imperfecta,
resulting in increased growth velocity and total body
mineral content, and fewer fractures, and cancer
patients who underwent high-dose chemotherapy,
accelerating bone-marrow recovery [31, 32]. The
immunomodulatory potential of MSC is currently
being tested for the treatment of Crohn's disease, in
which these cells could also contribute to the
regeneration of gastrointestinal epithelial cells [33].
MSC exhibit tropism for sites of tissue damage as
well as for the tumor microenvironment [34]. A
tumor has been defined as a “wound that never
heals” and many of the same inflammatory
mediators that are secreted by wounds are also
released in the tumor microenvironment and are
thought to be involved in attracting MSC to the
tumor site [35]. Cell migration is dependent on a
multitude of signals ranging from growth factors to
chemokines secreted by injured cells. MSC are
likely to have chemotactic properties similarly to
other immune cells that respond to signals
originating from injured and inflamed tissues [34].
Thus, the well-described model of leukocyte
migration can serve as a reasonable example to
facilitate the identification of factors involved in
MSC migration [34].
Once MSC reach the tumor microenvironment, they
integrate into the tumor-associated stroma
supporting cancer growth [35]. However, studies
investigating the in vivo and in vitro effects
mediated by MSC on tumor growth provided
conflicting results [36-40]. Depending on the
experimental model tested, either inhibition or
stimulation of tumor cell proliferation in vitro and/or
tumor growth in vivo have been reported.
Many different receptors have been implicated in the
homing of MSC: (1) up-regulation of chemokine
(CXC and CC) receptors (R) on the surface MSC
promoted by tissue-derived growth factors; (2)
activation of MSC associated Toll like receptors
(TLR) that target downstream expression of CXCR
and CCR; (3) up-regulation of MSC associated
adhesion molecules and integrins possibly involved
in paracrine cell movement [34]. The key players
implicated in MSC migration to date include the
chemokines CCL2, CXCL8, CCL5; LL-37, integrin
1, receptors CD44, CCR2, CCR3, and the receptor
tyrosine kinases for insulin growth factor (IGF)-1,
platelet derived growth factor (PDGF)-bb, HGF, and
vascular endothelial growth factor (VEGF) [34].
In this respect, an elegant paper showed that MSC
induce breast cancer cells to increase their metastatic
potential by secreting CCL5, which then acts in a
paracrine fashion on the tumor cells to enhance their
motility, invasion and metastasis [40].
The cancer tropism of MSC after systemic injection
provided a rationale for their development as
vehicles for tumor-specific delivery of genes
encoding antineoplastic molecules. Most studies
have demonstrated that MSC transfected with the
antineoplastic IFN- gene inhibit tumor growth and
angiogenesis in melanoma, breast cancer and glioma
models [41-44].
In conclusion, different data clearly support the
clinical use of MSC but some opportune cautions
about their uncontrolled use should also be used.
2. THE ROLE OF MESENCHYMAL
STEM CELLS IN THE HEMATOPOIE-
TIC-STEM-CELL NICHE
The bone marrow (BM) is the major site of adult
hematopoiesis, a process that is maintained by
specific interactions between hematopoietic and non
hematopoietic cells [45]. Hematopoietic stem cells
(HSCs) are self renewing multipotent progenitors
able to give rise to all types of mature blood cells,
whereas the non hematopoietic component is
comprised of stromal cells including osteoblasts,
endothelial cells, fibroblasts, reticular cells and
MSC. Stromal cells play a pivotal role in supporting
hematopoiesis [45]. An elegant work showed that
human MSC transplanted into the BM of
immunodeficient mice engraft, integrate in the
hematopoietic microenvironment and differentiate
into pericytes, myofibroblasts, osteocytes,
osteoblasts and endothelial cells [46]. All of these
cells constitute a specialized microenvironment of
the BM, known as HSC niche [45,47]. Two types of
HSC niches have been identified so far, the
endosteal niche composed of quiescent and
proliferating HSC, osteoblasts and stromal
progenitor cells, and the vascular niche formed by
endothelial cells, stromal cells and mobilized HSC
that have migrated to sinusoids following an
appropriate stimulus [1,45]. BM stromal cells
participate in the HSC maintenance, by regulating
the quiescence of the latter cells in the endosteal
niche and by controlling HSC proliferation,
differentiation and migration in the vascular
compartment [1, 45].
A recent study identified a new cell population of
stromal progenitors that localize in perivascular
areas of the BM, and are able to regenerate bone and
stroma and establish hematopoiesis in vivo [48].
These cells have the putative immunophenotype of
MSC together with high expression of melanomaassociated
cell adhesion molecule MCAM/CD146,
angiopoietin-1 (Ang-1), and CXC-chemokine ligand
12 (CXCL12) [48]. Ang-1, the ligand of the Tie-2