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The Role of Mesenchymal Stem Cells in Angiogenesis Recent Advances in Angiogenesis and Antiangiogenesis, 2009 21 A Marrow B Calyces Renal Artery Renal Vein Ureter Superior Vena Cava frontal lobe Spleen Aorta Left lung Sylvian fissure temporal lobe pone Cortex Medulla Renal Pelvis Cortex Trachea Medulla carina central sulcus parietal lobe occipetal lobe Capsule Interlobular septum cerebellum medulla Thymic corpuscle Thymic lobule MSC Fig. (1). Origin and differentiation of mesenchymal stem cells. Panel A shows the main anatomical sites from which MSC can be isolated. Panel B shows the ability of MSC to differentiate into mesodermal cell lineages and the trans-differentiation process, through which MSC can differentiate in vitro into endodermal and ectodermal cell types. Dashed arrows indicate that trans-differentiation in vivo is still controversial. elucidated [17]. Other studies showed that MSC stimulated B cell proliferation and differentiation, possible as result of the different experimental conditions used [20]. MSC can also interact with cells of the innate immune system, including NK cells and DC [12-16]. Specifically, MSC inhibit the proliferation and cytotoxicity of resting NK cells and their cytokine production in vitro [12]. These effects are mediated by PGE-2, IDO and sHLA-G5 released by MSC [19,21,22]. Interestingly, MSC can be lysed by activated NK cells through the interaction of NKG2D (natural-killer group 2 , member D) expressed by NK cells and its ligands ULBP3 (UL16 binding protein 3) or MICA (MHC class I polypeptide-related sequence A) expressed by MSC, and of NK-associated DNAM1 (DNAX accessory molecule 1) with MSC-associated ligand PVR (poliovirus receptor) or nectin-2 [12, 13]. MSC down-regulate expression of costimulatory molecules on DC, inhibit their in vitro differentiation from monocytes and CD34 + progenitors, reduce proinflammatory cytokine secretion (IL-12 and tumor necrosis factor-) by myeloid DC and increase IL-10 secretion by plasmacytoid DC (pDC) [8,14-16]. The main factor involved in these latter effects is PGE-2. LUNG CELL EPITHELIAL CELL ECTODERM MUSCLE CELL GUT EPITHELIAL CELL NEURON FIBROBLAST CHONDROCYTE ADIPOCYTE OSTEOBLAST ENDODERM MESODERM Adapted from Uccelli A et al. Nature Reiews lmmunology, 2008, 8, 726-736 Human MSC are poorly immunogenic, in spite of constitutive human leukocyte antigen (HLA)-class I expressionand Interferon- (IFN-) inducible HLAclass II expression [23]. It has been reported that, in a narrow window of IFN- concentration, human MSC can exert antigenpresenting cell (APC) functions for HLA-class IIrestricted recall antigens, such as Candida albicans and Tetanus toxoid. MSC up-regulate their HLAclass II antigen expression by autocrine secretion of low IFN- levels; however, when IFN- concentration in culture increases, HLA-class II antigen expression is down-regulated and the APC function is inhibited [24]. Moreover, MSC do not trigger effector functions in activated cytotoxic T lymphocytes (CTL), inducing an abortive activation program in the latter cells [25]. A recent report showed that human MSC can process and present HLA class I-restricted viral or tumor antigens to specific CTL with a limited efficiency, likely because of some defects in the antigen processing machinery (APM) components. However, MSC are protected from CTL-mediated lysis through a mechanism that is partly sHLA-G-dependent [26]. The immunoregulatory functions of human MSC, coupled with their low immunogenicity, provide a
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
Page 2 and 3: Recent Advances in Angiogenesis and
Page 4 and 5: FOREWORD It has been known for a ve
Page 6 and 7: single proangiogenic protein. Howev
Page 8 and 9: v Vito Pistoia Head, Laboratory of
Page 10 and 11: 2 Recent Advances in Angiogenesis a
Page 12 and 13: 10 Recent Advances in Angiogenesis
Page 22 and 23: Thymus and Angiogenesis Recent Adva
Page 32 and 33: Role of Thymidine Recent Advances i
Page 34 and 35: Role of Stromal Cells Recent Advanc
Page 40 and 41: Tumor Targeting with Transgenic End
Page 44 and 45: Tumor Vascular Disrupting Agents Re
Page 50 and 51: Tumour Vascular Disrupting Agents R
Page 52: Index Recent Advances in Angiogenes

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