Hematopoietic Stem Cell Mobilization and Homing after Transplantation: The Role of MMP-2, MMP-9, and MT1-MMP
(a) Administration of a mobilizing agent such as G-CSF (1) expands the number of myeloid cells (neutrophils/granulocytes) in the bone marrow and promotes increased expression of proteolytic enzymes (including MMP-2, MMP-9, and MT1-MMP). (2) These enzymes disrupt interactions that retain HSPC in their BM niches (e.g., SDF-1/CXCR4, VCAM-1/VLA-4, kit ligand/c-kitR, ECM). (3) Subsequently, permeabilization of the endothelial barrier occurs with the granulocytes “paving the way” for the egress of HSPC. Chemoattractants in the blood (primarily bioactive lipids such as sphingosine-1 phosphate (S1P) and hepatocyte growth factor (HGF)) further potentiate mobilization of HSPC to the peripheral blood. (b) Priming molecules such as hyaluronic acid and thrombin (1) amplifiy the chemotactic responses of HSPC via CXCR4 towards SDF-1 produced by bone marrow stromal cells and (2) accumulate MT1-MMP on the cell migration front. (3) MT1-MMP promotes activation of MMP-2 that degrades ECM barriers allowing extravasation of HSPC across the sinusoid endothelium. (4) HSPC highly expressing in CXCR4 attaches to the SDF-1-rich endosteal niches of the bone marrow.
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