The ability of stem cells to traffic around the body and to search out sites suitable for haemopoiesis is well demonstrated by (a) the 'homing' of transplanted stem cells to the bone marrow and (b) the chemotherapy and cytokine-induced 'mobilization' of stem cells into the circulation. Homing involves transendothelial migration from the bloodstream into the marrow microenvironment, whereas mobilization involves detachment from the microenvironment and transendothelial migration in the reverse direction. Together, these processes may provide a paradigm for stem cell trafficking in general (Figure 1.2). They are likely to involve multifactorial processes involving chemokines, cytokines, adhesion molecules and matrix-degrading enzymes.
In vitro experiments have shown that stromal cell-derived chemokine gradients across an endothelial barrier induce stem cells to migrate from one side to the other. Chemokines are cytokines with direct chemotactic effects on receptor-expressing target cells. However, stromal cell-derived factor 1 (SDF-1) is the only chemokine that acts on haemopoietic stem and progenitor cells. Once the stem cells have gained the extravascular spaces in the bone marrow, the stromal cells provide a plethora of potential sites for recognition by stem cells, including cell surface and extracellular matrix ligands for adhesion molecules (CAMs) on the stem cell surface. Haemopoietic stem and progenitor cells express a wide variety of cell adhesion molecules of different classes (e.g. selectins and integrins), but they are not specific for stem cells as they are also expressed by mature leucocytes.
Homing/mobilized . .
\ Transmigrating stem cell
Immobilized stem cell
Extracellular matrix r
Immobilized stem c
Cell adhesion r matrix 1 ^molecule and ligand
Figure 1.2 Stages in the homing and mobilization of stem cells.
Cytokines and cytokine receptors may also act in cytoadhesion as stem cell factor (SCF; c-Kit ligand) is expressed on the cell surface by stromal cells and its receptor, c-Kit, is expressed by stem cells. Similarly, the Notch ligand, Jagged, is expressed by stromal cells, whereas Notch is expressed by stem cells.
Clearly, cytokines play a role in the release of stem cells from the marrow microenvironment as cytokine administration is used to induce stem cell mobilization into the peripheral blood. Cytokines increase metalloproteinase expression, release stem cell factor from the stromal cell surface and induce stem cell migration through the endothelial barrier. Thus, stem cell trafficking may be a dynamic and continuous process, depending on the prevailing haemopoietic activity.
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