2004 Volume 50 Issue 1 Pages 17-25
In adults, stem cells are localized within the bone marrow (BM) microenvironment, where they exist in either a quiescent state or are instructed to proliferate, differentiate and mobilize to the circulation following specific physiological stresses. However, the mechanism for the recruitment of such stem cells as endothelial and hematopoietic stem cells (HSCs) from the BM microenvironment is not known. We show that matrix metalloproteinase-9 (MMP-9), induced in BM stromal cells, is the key factor in releasing soluble Kit-ligand (sKit-1) enabling the transfer of stem cells from the quiescent to the proliferative niche. Administration of cell mobilizing factors including not only hematopoietic growth factors but also angiogenetic factors or chemokines results in upregulating MMP-9 expression, which then causes shedding of sKit-1 and recruitment of stem cells. In MMP-9-/-mice, release of sKit-1, cell cycling and motility of HSCs is profoundly impaired, resulting in failure in hematopoietic recovery and increased mortality after BM suppression. Exogenous sKit-1 restores hematopoiesis and survival of BM ablated MMP-9-/-mice. Thus, release of sKit-1 by MMP-9 in response to stress enables HSCs to translocate to a permissive niche favoring proliferation, differentiation, mobilization and reconstitution of the stem cell pool.
