Laminins and Fibulins in Bone Marrow

Sammanfattning: Development of hematopoietic cells in bone marrow takes place in association with the hematopoietic microenvironment. Extracellular matrix (ECM) molecules and stromal cells in bone marrow provide a structural environment for hematopoietic cells, but they also directly influence proliferation, differentiation and migration of cells by signal transduction mediated by ligand binding to cell surface adhesion receptors. Laminins are ECM proteins, which influence cellular phenotype and functions via integrins and other receptors. We found that the laminin isoforms, laminin-8 (alpha 4 beta 1 gamma 1) and laminin-10 (alpha 5 beta 1 gamma 1) were expressed in bone marrow at sites of hematopoietic cell development and migration. In functional assays, laminins containing the alpha 5 chain (laminin-10/11) and the alpha 4 chain (laminin-8) were adhesive for a mouse multipotent progenitor cell line, isolated human hematopoietic stem and progenitor cells (CD34+CD38- and CD34+), and more differentiated human hematopoietic cells. Most human bone marrow stem and progenitor cells expressed the integrin alpha 6 chain. The integrin alpha 6 beta 1 receptor mediated adhesion of these cells to both laminin isoforms. Both laminin-8 and laminin-10/11 facilitated transmigration of human CD34+ cells by an integrin alpha 6 mediated mechanism, and laminin-10/11 in addition promoted proliferation of CD34+ progenitor cells, suggesting a physiological role of laminins during hematopoiesis. We also studied the expression of ECM proteins, fibulin-1 and fibulin-2 in bone marrow. A high degree of co-localization of fibulins with a major bone marrow cell adhesive ECM protein, fibronectin, was found in cultured bone marrow stroma. This suggests that fibulins might influence cell adhesion to fibronectin in bone marrow. Glucocorticoids down-regulated expression of several ECM proteins in bone marrow, including fibronectin, fibulin-1, and fibulin-2, suggesting that one of the mechanisms through which glucocorticoids regulate hematopoiesis may be by modifying the ECM in bone marrow stroma.