HSC fate decisions are regulated by cellintrinsic and cell-extrinsic cues. The latter cues are derived from the BM niche. Membrane-type 1 matrix metalloproteinase (MT1-MMP), which is best known for its proteolytic role in pericellular matrix remodeling, is highly expressed in HSCs and stromal/niche cells. We found that, in MT1-MMP ؊/؊ mice, in addition to a stem cell defect, the transcription and release of kit ligand (KitL), stromal cell-derived factor-1 (SDF-1/CXCL12), erythropoietin (Epo), and IL-7 was impaired, resulting in a trilineage hematopoietic differentiation block, while addition of exogenous KitL and SDF-1 restored hematopoiesis. Further mechanistic studies revealed that MT1-MMP activates the hypoxia-inducible factor-1 (HIF-1) pathway via factor inhibiting HIF-1 (FIH- 1
IntroductionThe adult hematopoietic system is maintained by a small number of HSCs that reside in the BM in a specialized microenvironment (the niche). 1,2 Here, HSCs undertake fate decisions including differentiation to progenitor cells and self-renewal, which ensures a lifelong supply of terminally differentiated blood cells. Intrinsic cellular programming and external stimuli such as adhesive interactions with the microenvironmental stroma and cytokine activities regulate HSC fate. However, it is unclear how niche factor production is controlled to adjust to external demand with a fine-tuned response.Hypoxia-inducible factors (HIFs) consist of an ␣ (HIF-␣) and a  (HIF-, or ARNT) subunit and activate the expression of genes encoding proteins that regulate cell metabolism, motility, angiogenesis, hematopoiesis, and other functions. HSCs maintain cell-cycle quiescence by regulating HIF-1␣ levels. 3,4 Mice with mutations in the heterodimeric transcription factor HIF develop extensive hematopoietic pathologies: embryos lacking Arnt have defects in primitive hematopoiesis. 5 Mice lacking endothelial PAS domain protein 1 (EPAS1, also known as HIF-2alpha/HRF/HLF/MOP3), a second HIF family member, exhibited pancytopenia, and it was shown that EPAS1 is necessary to maintain a functional microenvironment in the BM for effective hematopoiesis. 6 HIFs bind to canonical DNA sequences in the promoters or enhancers of target genes such as erythropoietin (Epo), vascular endothelial growth factor-A, SDF-1␣/CXCL12, angiopoietin-2, platelet-derived growth factor-B and Kit Ligand (KitL)/stem cell factor, which are involved in HSC maintenance within the BM niche. 7-10 The chemokine SDF-1␣/CXCL12 (SDF-1␣) is expressed by perivascular, endosteal, mesenchymal stem and progenitor cells as well as by osteoblasts. 11,12 SDF-1␣ deficiency leads to a reduction in HSCs and impaired B-cell development in mice. 13,14 IL-7 is another stromal cell-derived niche factor, which, in cooperation with CXCL12, functions at sequential stages of B-cell development. 15,16 IL-7 or IL-7R deficiency results in impaired B-cell development. 17,18 Proteases such as matrix metalloproteinase-9 (MMP-9) and the serine proteinase plasmin(ogen) regulate HSC fate through KitL release i...