6.2. Osteogenesis

Two bone morphogenic proteins (BMPs), especially BMP-2 and BMP-6, stimulate osteogenesis in MSCs. BMP-2 acts by induction the p300-mediated acetylation of Runx2, a master osteogenic gene, which leads to enhanced Runx2 transactivating capability. Histone deacetylases 4 and 5 stimulate the degradation of Runx2 by deacetylation, through Smurf1, Smurf2 and E3 ubiquitin ligases [21]. The cytokine TNF-α, involved in inflammation-mediated bone degradation, downregulates Runx2protein levels by increasing degradation by Smurf1 and Smurf2. BMPs, Runx2, and histone deacetyltransferases that are responsible for the therapeutic approaches to MSC-based bone tissue engineering, stimulate existing TNF-α based immunotherapy of bone diseases.

Wnts is another important modulator in osteogenesis. Knockout and dosage compensation in Wnt-pathway-related transgenic animals provide the strongest proof that high levels of endogenous Wnts promote osteogenesis, whereas low levels inhibit osteogenesis [22].

The exciting finding of transcriptional mechanisms, suggesting that a global osteogenic gene, runx2, and a specific osteogenic homeobox gene, tbx5, are responsible for the balance of bone formation and loss, show two strong models of transcriptional regulation of osteogenesis, and potentially other MSC lineage differentiation programs.

Thereby, gene-knockout or blocking of TLR-4 on MSCs can produce improved infiltration of

Stromal Stem Cells: Nature, Biology and Potential Therapeutic Applications

http://dx.doi.org/10.5772/intechopen.77346

9

In myocardium damage, Stromal cell-derived factor-1α (SDF-1) is a chemokine that mediates the homing of the endogenous MSCs. An intracellular storage of the receptorCXCR4 present in 80–90% of hMSCs but not expressed in large amounts on the surface. When it is expressed by mRNA nucleofection, Ca2+ signaling is stimulated through its ligand SDF-1α [28]. However, in dilated cardiomyopathy (DCM), another homing factor of MSCs, monocyte-chemotactic protein-1 (MCP-1), has been established because of the presence of chemokine receptor type 2 (CCR2), a MCP-1 receptor, on the cell surface [29]. Many in-vivo and in-vitro studies have been performed to comprehend the mechanism of MSC recruitment to the site of the damaged tissue, starting the process of repair along with its protective role. For the regenerative process to occur, MSCs either

Beside cell-to-cell contact, the MSCs secret many factors including EVs and soluble factors modulating the inflammatory response. The main paracrine factors are TGF-β, prostaglandin E2 (PGE2), hepatocyte growth factor (HGF), IL-10, IL-6, indoleamine 2,3-dioxygenase (IDO), nitric oxide (NO), and human leukocyte antigen G (HLA-G). Each of these factors plays an important role in regulation of different target immune cells. Other than such soluble factors, MSCs secrete extracellular vehicles (EVs), lipid bilayers that contain and transport the cytoplasmic components of the MSCs. EV is an inclusive term that has recently been suggested to encompass both exosomes and microvesicles. The immunological potential of MSC EVs in vitro, and the ability

of these EVs to attenuate an activated immune system in vivo have been reported [31].

mediated cytolysis and decreases interferon-gamma (IFN-γ) secretion [32].

MSCs are capable of inhibiting proliferation and function of NK cells, mediated by IDO, PGE2, and TGF-β1. Many studies have reported that MSCs only partially inhibit the proliferation of activated NK cells and are susceptible to lysis by activated cells. HLA-G5 inhibits NK cell

Dendritic cells are antigen presenting cells that arise from monocytes or CD34+ hematopoietic stem cells. After exposure to antigens, they are turned into mature cells. MSCs impair this

Chemotaxis attracts neutrophils to the wound site, traversing post capillary venules to lyse pathogens with the granules within phagolysosomes, and then undergo apoptosis. MSCs secrete

7.1. Natural killer (NK) cells

7.2. Dendritic cells (DCs)

7.3. Neutrophils

differentiation process via PGE2 secretion [33].

MSCs to the damaged tissue, thus, raising the efficacy of MSC-based therapy [27].

differentiate into beating cardiomyocytes or promote a paracrine effect [30].

7. The immunomodulatory effects of mesenchymal stem cells

#### 6.3. Adipogenesis

MSC adipogenesis is stimulated by the nuclear hormone receptor peroxisome proliferatoractivated receptor γ (PPARγ) but at the same time it represses osteogenesis. Through binding to various ligands, like long-chain fatty acids and thiazolidinedione compounds, PPARγ induces the transactivation and transrepression of PPARγ. The bipotent coregulators TAZ function as a coactivator of Runx2 and as a corepressor of PPARγ, thus promoting osteogenesis while blocking adipogenesis [23]. In general, osteogenic genes are corepressed by a coactivator of adipogenic genes, but the opposite is also possible. This type of cellular efficiency is very likely, allowing that MSCs may be differentiated to both lineages.

Stretch-related mechanoinduction represents another interesting example of exchange between transcriptional cofactors of adipogenesis. If stretch is induced on mouse embryonic lung mesenchymal cells they form myocytes but they form adipocytes if uninduced. This occurs through activation of specific isoforms of tension-induced/inhibited proteins (TIPs) [24] chromatin-modifying proteins with intrinsic HAT activity that have other distinctive domains such as nuclear receptor-interacting motifs. TIP-1 which is expressed under nonstretch conditions provides a potential mechanistic endpoint for cytoplasmic RhoA-mediated of adipogenesis; induces RhoA signaling which stimulates adipogenesis [25]. Whereas TIP-3 induces myogenesis. These findings propose a molecular model that connects cell morphology mechanical induction cytoskeletal signaling and transcriptional response during MSC adipogenesis induction.

#### 6.4. Myogenesis

The majority of studies of myogenesis in adult stem cells target skeletal muscle-derived stem cells, or satellite cells. The highly successful stimulation of myogenesis from adult stromal MSCs happened after transfection with activated Notch 1. Other studies, mainly target cardiomyogenesis, represented the importance of cell-cell contact in stimulating cardiomyogenesis through cocultured MSCs and cardiomyocytes, and the stimulation of MSC cardiomyogenesis in a rat intramyocardial infarct model by Jagged 1, a Notch ligand [26].

In normal conditions, the MSCs are present in low numbers, and on induction of myocardial infarction (MI) these cells proliferate rapidly to participate in wound healing, by generation of fibroblasts and myofibroblasts.

After MI, MSCs penetrate the injured tissue by trafficking through the ECM and repairing the cardiac function. This is through production of HGF by apoptotic cardiomyocytes, and not by necrotic cardiomyocytes. MSCs are attracted to the apoptotic cell death site by HGF receptor MET, which are responsible for activation of a wide range of signaling pathways. Platelets migrate MSCs to the apoptotic cardiac cells by means of the interaction of a nuclear protein with TLR-4 expressed on MSCs; high mobility group box-1 (HMGB1). On activation of platelet, HMGB1/TLR-4 downregulate MET on MSCs, thus, decreasing the recruitment of the cells. Thereby, gene-knockout or blocking of TLR-4 on MSCs can produce improved infiltration of MSCs to the damaged tissue, thus, raising the efficacy of MSC-based therapy [27].

In myocardium damage, Stromal cell-derived factor-1α (SDF-1) is a chemokine that mediates the homing of the endogenous MSCs. An intracellular storage of the receptorCXCR4 present in 80–90% of hMSCs but not expressed in large amounts on the surface. When it is expressed by mRNA nucleofection, Ca2+ signaling is stimulated through its ligand SDF-1α [28]. However, in dilated cardiomyopathy (DCM), another homing factor of MSCs, monocyte-chemotactic protein-1 (MCP-1), has been established because of the presence of chemokine receptor type 2 (CCR2), a MCP-1 receptor, on the cell surface [29]. Many in-vivo and in-vitro studies have been performed to comprehend the mechanism of MSC recruitment to the site of the damaged tissue, starting the process of repair along with its protective role. For the regenerative process to occur, MSCs either differentiate into beating cardiomyocytes or promote a paracrine effect [30].
