Distinct Roles for Matrix Metalloproteinases 2 and 9 in Embryonic Hematopoietic Stem Cell Emergence, Migration, and Niche Colonization

Hematopoietic stem/progenitor cells (HSPCs) are formed during ontogeny from hemogenic endothelium in the ventral wall of the dorsal aorta (VDA). Critically, the cellular mechanism(s) allowing HSPC egress and migration to secondary niches are incompletely understood. Matrix metalloproteinases (MMPs) are inflammation-responsive proteins that regulate extracellular matrix (ECM) remodeling, cellular interactions, and signaling. Here, inhibition of vascular-associated Mmp2 function caused accumulation of fibronectin-rich ECM, retention of runx1/cmyb+ HSPCs in the VDA, and delayed caudal hematopoietic tissue (CHT) colonization; these defects were absent in fibronectin mutants, indicating that Mmp2 facilitates endothelial-to-hematopoietic transition via ECM remodeling. In contrast, Mmp9 was dispensable for HSPC budding, being instead required for proper colonization of secondary niches. Significantly, these migration defects were mimicked by overexpression and blocked by knockdown of C-X-C motif chemokine-12 (cxcl12), suggesting that Mmp9 controls CHT homeostasis through chemokine regulation. Our findings indicate Mmp2 and Mmp9 play distinct but complementary roles in developmental HSPC production and migration. [Display omitted] •Mmp2 function is required for completion of EHT and HSPC egress from the VDA•Mmp2 controls EHT via remodeling fibronectin-rich extracellular matrix in the VDA•Mmp9 activity is necessary for migration between secondary hematopoietic niches•Mmp9 influences Cxcl12 signaling to control CHT vascularity and HSPC colonization Theodore and colleagues illustrate essential yet distinct roles for inflammation-induced matrix metalloproteinase 2 (Mmp2) and Mmp9 in developmental hematopoiesis. Mmp2 facilitates hematopoietic stem and progenitor cell (HSPC) budding and egress from the ventral dorsal aorta by regulating extracellular matrix fibronectin accumulation; in contrast, Mmp9 modifies Cxcl12/Cxcr4 signaling to enable HSPC colonization of, localization within, and migration between, secondary hematopoietic niches.