Loss of endothelial membrane KIT Ligand affects systemic KIT ligand levels but not bone marrow hematopoietic stem cells.

A critical regulatory role of hematopoietic stem cell vascular niches in the bone marrow has been implicated to occur through endothelial niche cell expression of KIT Ligand. However, endothelial-derived KIT Ligand is expressed in both a soluble and membrane-bound form, and not unique to bone marrow niches and is also systemically distributed through the circulatory system. Here we confirm that upon deletion of both the soluble and membrane-bound form of endothelial-derived KIT Ligand hematopoietic stem cells are reduced in mouse bone marrow. However, deletion of endothelial-derived KIT Ligand was also accompanied by reduced soluble KIT Ligand levels in blood, precluding any conclusion as to whether the reduction in HSC numbers reflect reduced endothelial expression of KIT Ligand within HSC niches, elsewhere in the bone marrow and/or systemic sKIT Ligand produced by endothelial cells outside of the bone marrow. Notably, endothelial deletion specifically of the membrane bound form of KIT Ligand also reduced systemic levels of soluble KIT Ligand although with no effect on stem cell numbers, implicating a hematopoietic stem cell regulatory role primarily of soluble rather than membrane KIT Ligand expression in endothelial cells. In support of a role of systemic rather than local niche expression of soluble KIT Ligand, hematopoietic stem cells were unaffected in bones with deletion of KIT ligand when implanted in mice with normal systemic levels of soluble KIT Ligand. Our findings highlight the need for more specific tools to unravel niche-specific roles of regulatory cues expressed in hematopoietic niche cells in the bone marrow.