Hematopoietic Stem Cell Mobilization and Homing after Transplantation: The Role of MMP-2, MMP-9, and MT1-MMP

Abstract

Hematopoietic stem/progenitor cells (HSPCs) are used in clinical transplantation to restore hematopoietic function. Here we review the role of the soluble matrix metalloproteinases MMP-2 and MMP-9, and membrane type (MT)1-MMP in modulating processes critical to successful transplantation of HSPC, such as mobilization and homing. Growth factors and cytokines which are employed as mobilizing agents upregulate MMP-2 and MMP-9. Recently we demonstrated that MT1-MMP enhances HSPC migration across reconstituted basement membrane, activates proMMP-2, and contributes to a highly proteolytic bone marrow microenvironment that facilitates egress of HSPC. On the other hand, we reported that molecules secreted during HSPC mobilization and collection, such as hyaluronic acid and thrombin, increase MT1-MMP expression in cord blood HSPC and enhance (prime) their homing-related responses. We suggest that modulation of MMP-2, MMP-9, and MT1-MMP expression has potential for development of new therapies for more efficient mobilization, homing, and engraftment of HSPC, which could lead to improved transplantation outcomes.

Figure 1

(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.