Recent Advances in Angiogenesis and ... - Bentham Science

20 Recent Advances in Angiogenesis and Antiangiogenesis, 2009, 20-29
CHAPTER 3
The Role of Mesenchymal Stem Cells in Angiogenesis
Lizzia Raffaghello and Vito Pistoia
Laboratory of Oncology, G. Gaslini Children Hospital, Genova, Italy
Address correspondence to:Lizzia Raffaghello, Ph.D; Laboratory of Oncology, G. Gaslini Institute, Largo G.
Gaslini 5, 16148 Genova, Italy; Phone and fax: +39-010-3779820; e-mail: lizziaraffaghello@ospedalegaslini.ge.it
Abstract: Mesenchymal stem cells (MSC) are a heterogeneous subset of stromal stem
cells that can be isolated from many adult tissues. They can differentiate into cells of the
mesodermal lineage, such as adipocytes, osteocytes and chondrocytes, providing a
promising tool for tissue repair. MSC can interact with cells of both the innate and
adaptive immune systems, leading to the modulation of several effector functions. The
immunoregulatory functions of human MSC, coupled with their low immunogenicity,
provide a rationale for the use of allogeneic MSC to treat severe graft-versus-host disease
(GvHD) and, possibly, autoimmune disorders. In addition, MSC exhibit tropism for sites
of tissue damage as well as for the tumor microenvironment, where they integrate into the
tumor-associated stroma supporting cancer growth. However, studies investigating the in
vivo and in vitro effects mediated by MSC on tumor growth provided conflicting results,
depending on the experimental model tested. This chapter reviews the role of MSC in
different angiogenic processes and underlying mechanisms. In particular, we discuss the
involvement of MSC in angiogenesis in ischemic brain and heart after stroke, wound
healing, tumor angiogenesis and maintenance of hematopoietic stem cell niche.
1. MESENCHYMAL STEM CELLS:
FEATURES AND FUNCTIONS
About 40 years ago Friedestein first identified
multipotent stromal cells in the bone marrow. These
cells were spindle shaped, adhered to plastic, and
proliferated to form colonies representing the
progenies of single colony forming units-fibroblastic
(CFU-F) [1]. CFU-F derived stromal cells
differentiated under defined in vitro conditions into
multiple cell types including osteoblasts,
chondrocytes, and adipocytes [1]. Later on, the
definition of bone marrow-derived stromal cells as
mesenchymal stem cells (MSC) was proposed [2].
Although the bone marrow represents the most
common site from which MSC are isolated, these
cells have also been found in many other human
tissues (Fig. 1A) [3]. MSC are able to self renew and
to differentiate towards mesodermal lineages in vivo,
representing a promising tool for tissue repair.
Moreover, MSC can differentiate into cells of other
lineages
in vitro (muscle cells, hepatocytes,
endothelial cells, and neurons), through a process
called trans-differentiation (Fig. 1B) [4].
MSC cultured in vitro lack specific and unique
markers. There is now consensus agreement MSC
express variable levels of CD105 (endoglin), CD73
(ecto-5’-nucleotidase), CD44, CD90, CD71
(transferring receptor), the ganglioside GD2 and
CD271 (low affinity nerve growth factor receptor),
and lack expression of hematopoietic markers
Domenico Ribatti (Ed.)
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CD45, CD34, CD14 or costimulatory molecules
CD40, CD80, CD86 [as reviewed in 1].
One of most the most intriguing features of MSC is
their ability to escape immune recognition and
inhibit immune responses [1,5,6].
Specifically, MSC mediate immunoregulatory
activities by inhibiting the functions of different
immune cells including T and B lymphocytes,
Natural Killer (NK) cells and dendritic cells (DC)
[7-17]. MSC were found to inhibit CD4 + and CD8 +
T-cell proliferation and functions, induce anergy in
naïve T cells, and promote expansion of
immunosuppressive regulatory T cells [6-8].
Inhibition of T cell proliferation by MSC appears to
depend on both cell-to-cell interaction and the
release of soluble factors. In this respect,
transforming growth factor-1 (TGF-1) and
hepatocyte growth factor (HGF), indoleamine 2,3dioxygenase
(IDO) and prostaglandin E-2 (PGE-2)
represent the main MSC-derived molecules that
have been proposed to exert immunomodulatory
activity on CD4 + T cells [6, 8,18]. Inhibition of
CD8 + T-cell cytotoxicity and induction of T
regulatory cell differentiation are partly related to
the release of soluble (s) HLA-G [19].
The second cell type involved in adaptive immune
responses is the B cell, whose proliferation and
differentiation are inhibited by MSC [17]. These
effects seem to be related to cell-cell contact and
soluble factors, but the exact mechanism is still not