Mesenchymal stem cells

Mesenchymal stem cells (MSCs) are multi-potent cells with a strong capacity for self-renewal. They are capable of multilineage differentiation into mesoderm-type cells such as osteoblast, adipocyte, chondrocyte and possibly, but still controversial, other non-mesoderm type cells, for example, neuronal cells or hepatocytes. (Abdallah et al., 2008) (Figure 8)

They can be isolated from a variety of tissues, such as bone marrow, adipose tissue, umbilical cord, and umbilical cord blood. MSCs have the ability to differentiate into a variety of cell types, depending on cues from their microenvironment. MSCs are identified by the expression of many molecular markers, such as: CD105, CD73 and are negative for the hematopoietic markers CD34, CD45, CD14. (Daminici et al., 2006)

An important property of MSCs is their capacity for migration and homing in or around the zones damaged by ischemia, inflammation, and trauma or tumour sites. Understandably, the efficacy and time course of cell invasion into the damaged tissues depends upon the route of transplantation. (Kholodenko et al., 2013)

MSCs have great potential as therapeutic agents, since they can be obtained fairly effortlessly and can be rapidly expanded ex vivo for autologous transplantation, according to Dharmasaroja et al, (2009).

Figure 8 Variety of tissue types msCs have the potential to differentiate into, depending on signals produced by the local physiological environment. (Kishk et al., 2010)

Migratory mechanisms of msCs

Imitola et al., (2004) show that neural stem cells (NSCs) migrate in vivo toward an infarcted area, where surviving local astrocytes, microglia and endothelium up-regulate the inflammatory chemoattractants, including SDF-1α, which direct the migration of NSCs towards the penubmra. Both exogenous and endogenous NSCs express the cognate receptor for SDF-1α, CXCR4, which allows them to migrate towards the source of chemokines, home to the ischaemically damaged region and produce anti-inflammatory and anti-scarring molecules. (Figure 10)

Bhakta et al., (2006) state that most MSCs do not possess CXCR4, however, to optimize their migration and survival, CXCR4 gene can be expressed using retroviral transduction. In this study, MSCs were isolated from healthy volunteers, cultured and transduced with either a CXCR4 containing retroviral vector and green fluorescent protein (GFP) or only GFP - control vector. As expected, MSCs transduced with CXCR4 migrated significantly more toward SDF-1α. (Figure 11) Findings by Cheng et al., (2008) also support this statement.

Figure 10 Model of SDF-1α - directed homing of CXCR4+ NSCs toward pathology (Imitola et al., 2004)

Figure 11 MSCs transduced with the CXCR4 vector, compared to MSCs transduced with the control vector (GFP) demonstrated significantly more migration to SDF-1 α after both 3 and 6 hours. (Bhakta et al., 2006)

Matrix metalloproteinase-9 (MMP-9) is involved in the motility of stem cells by degrading components of the extracellular matrix. MMP-9 suppression reduced stem cells migration in the infarcted brain. Therefore, both stromal cell-derived factor-1α and MMP-9 expression appear to be essential for the homing ability of stem cells. (Tsai et al., 2011) The study has also found that priming MSCs with VPA or lithium increased homing to the cerebral infarcted regions via CXCR4 and MMP-9 upregulation, and copriming with VPA and lithium further enhanced this effect. MSC were labeled with BrdU before transplantation. Homing MSCs were detected using immunohistochemistry. (Figure 12)

Figure 12 Priming with VPA and/or lithium promotes MSC (green) homing into infarcted brain regions. In the ischemic frontal cortex (A) and striatum (B), the number of BrdU-positive cells increased when MSC were primed with sodium VPA and/or lithium chloride before transplantation. (Tsai et al., 2011)