In the development of stem cell-based therapeutic platforms for tissue regeneration, the selection of which type of stem cell to use will be enormously important. Adult mesenchymal stem cells (MSCs) are considered one of the most promising tools for cell and cell-based gene therapy in bone repair (Gafni et al., 2004). Adult MSCs have been shown to possess the potential to differentiate into several lineages including bone, cartilage, fat, tendon, muscle, and marrow stroma (Haynesworth et al., 1992; Mackay et al., 1998; Yoo et al., 1998; Young et al., 1998; reviewed by Caplan and Bruder, 2001). The best known source of MSCs in adult humans is the bone marrow (BM) compartment; this region contains several types of cells, including those of the hematopoietic lineage as well as endothelial cells (ECs) and MSCs that are part of the marrow stromal system (Pittenger et al., 1999). Other sources of MSCs have also been identified, such as fat tissue (Zuk et al., 2001, 2002), cord blood (Hong et al., 2005; Jeong et al., 2005; Moon et al., 2005), and peripheral blood, although the latter finding is still controversial (Fernandez et al., 1997; Conrad et al., 2002).

Several protocols were recently established to enable regeneration of large bone defects by using human MSCs (hMSCs) that have been expanded in culture. These cells differentiate into osteogenic cells and, as vehicles, deliver a therapeutic gene product such as one of the bone morphogenetic proteins (BMPs) (Turgeman et al., 2001; Peterson et al., 2005; reviewed by Gamradt and Lieberman, 2004). It has been shown that in combination with BMP-2, hMSCs are able to heal full-thickness nonunion bone defects (Turgeman et al., 2001; Dragoo et al., 2003). In addition, Lee et al. (2001) have demonstrated that, following transduction with retroviral vectors, in vivo implantation, and differentiation, hMSCs can maintain stable expression of the therapeutic gene. In these studies, MSCs were isolated from BM, expanded in culture (in some cases genetically engineered) and implanted in vivo. Reports of these studies and many others have emphasized the benefit of MSCs as vehicles for cell-mediated gene therapy in the field of orthopedics (Gafni et al., 2004). In addition, MSCs have been implemented in regeneration of the heart (cardiac muscle and vascular system), skeletal muscle, nerve, liver, and pancreas, with regeneration of cardiac tissue being foremost (Burt et al., 2002; Lardon et al., 2002; Bonafe et al., 2003; Dabeva et al., 2003; Abedin et al., 2004; Kim et al., 2004; Jain et al., 2005; Sonoyama et al., 2005; Goncalves et al., 2006).

In cell-based therapies, the culture expansion stage is extremely costly and time consuming, and in many cases cells may lose their multipotentiality in vivo and fail to meet the desired goal. Rubio et al. (2005) reported that cultured hMSCs can undergo spontaneous transformation as a consequence of in vitro expansion. In very few articles has the use of noncultured freshly isolated hMSCs been described. Recently, CD105+ hMSCs were isolated from BM and were shown to exhibit in vivo osteogenic potential prior to in vitro expansion suggesting the utilization of these cells as freshly isolated population and avoiding the culture-expansion stage (Aslan et al., 2006b). Horwitz et al. (1999) showed that hMSCs present in unprocessed BM allografts engraft and may provide a stem cell reservoir for the differentiation and renewal of osteoblasts. The enrichment of mesenchymal progenitors, derived from fresh BM aspirates, in cancellous bone matrices has been found to increase bone formation and the bone union score significantly in a spinal fusion model (Muschler et al., 2003). Rombouts and Ploemacher have demonstrated that culture expansion attenuates the homing ability of MSCs after systemic infusion in irradiated mice (Rombouts et al., 2003). This indicates that MSCs may lose some of their natural stem cell characteristics following expansion in vitro. Other investigators have proposed that all known characteristics of MSCs may be an outcome of the culture stage and do not really represent the actual characteristics of MSCs residing in vivo at the BM niche (Javazon et al., 2004).

The isolation of an hMSC-enriched population requires an efficient and reproducible method. Few methods have been described for the isolation of MSCs, including enhancement of the plastic-adherence property of the cells by using selected amounts of fetal calf serum (FCS) (Kadiyala et al., 1997; Pittenger et al., 1999) and immunomagnetic isolation based on the presence of the STRO-1 surface molecule (Gronthos et al., 1995, 2003). These methods have not been used in any study to show the differentiation potential of cells before culture expansion.

In the study conducted by Majumdar et al. (2000), the anti-CD105 (endoglin) antibody was used to isolate cells from human BM aspirates; after expansion in culture these cells differentiated in vitro into chondrogenic cells and displayed an immunophenotype distinctive to hMSCs. We recently reported that we used the CD105-based immunoisolation method to obtain a fresh noncultured population of hMSCs and to determine these cells' osteogenic potential both in vitro and in vivo. Our results demonstrate that this noncultured population of adult stem cells can be genetically engineered and induced to undergo osteogenic differentiation in vivo thus showing the cells' potential to serve as an attractive therapeutic tool for bone regeneration purposes (Aslan et al., 2006b).

One striking feature of MSC therapy is the cumulative data on the tolerance shown by the host to allogeneic MSCs. The mechanisms by which this immunotolerance exist are complex and have not yet been thoroughly identified. It has been shown that there is a low expression of alloantigens by MSCs, and this might involve cell contact-dependent or -independent pathways, which are modulated by secretion of soluble factors such as interleukin (IL)-2 and IL-10, transforming growth factor-beta1 (TGF1), prostaglandin E2 (PGE2), and hepatocyte growth factor (HGF) among others. Immune system cells, such as dendritic cells (DCs) and T-cells, have also been shown to be affected by the presence of MSCs in mixed lymphocyte cultures (MLCs) (Beyth et al., 2005). In addition to the advantage that these cells offer the field of regenerative medicine, MSCs provide prophylaxis against graft-versus-host disease in cases of allogeneic hematopoietic stem cell (HSC) transplantation.

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Mesenchymal Stem Cell - an overview | ScienceDirect Topics

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