Endothelial Jagged-1 Is Necessary for Homeostatic and Regenerative Hematopoiesis

• Published in: Cell reports (Cambridge) 2013-09, Vol.4 (5), p.1022-1034
• Main Authors: Poulos, Michael G., Guo, Peipei, Kofler, Natalie M., Pinho, Sandra, Gutkin, Michael C., Tikhonova, Anastasia, Aifantis, Iannis, Frenette, Paul S., Kitajewski, Jan, Rafii, Shahin, Butler, Jason M.
• Format: Article
• Language: English
• Subjects: Animals; Calcium-Binding Proteins - metabolism; Endothelial Cells - cytology; Endothelial Cells - metabolism; Hematopoiesis - physiology; Homeostasis; Intercellular Signaling Peptides and Proteins - metabolism; Jagged-1 Protein; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Serrate-Jagged Proteins; Signal Transduction
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.07.048

The bone marrow (BM) microenvironment is composed of multiple niche cells that, by producing paracrine factors, maintain and regenerate the hematopoietic stem cell (HSC) pool (Morrison and Spradling, 2008). We have previously demonstrated that endothelial cells support the proper regeneration of the hematopoietic system following myeloablation (Butler et al., 2010; Hooper et al., 2009; Kobayashi et al., 2010). Here, we demonstrate that expression of the angiocrine factor Jagged-1, supplied by the BM vascular niche, regulates homeostatic and regenerative hematopoiesis through a Notch-dependent mechanism. Conditional deletion of Jagged-1 in endothelial cells (Jag1(ECKO) mice) results in a profound decrease in hematopoiesis and premature exhaustion of the adult HSC pool, whereas quantification and functional assays demonstrate that loss of Jagged-1 does not perturb vascular or mesenchymal compartments. Taken together, these data demonstrate that the instructive function of endothelial-specific Jagged-1 is required to support the self-renewal and regenerative capacity of HSCs in the adult BM vascular niche. [Display omitted] •Endothelial Jagged-1 maintains the HSC pool by interfering with Notch signaling•Endothelial-specific deletion of Jagged-1 inhibits ex vivo expansion of HSCs•Hematopoietic regeneration following stress is dependent on endothelial Jagged-1•Endothelial Jagged-1 regulates HSC quiescence and self-renewal capacity The role of Notch signaling in the regulation of adult hematopoiesis has long been a subject of debate. Here, Rafii, Butler, and colleagues demonstrate that endothelial-specific expression of Jagged-1 is critical in maintaining adult hematopoiesis, whereas quantification and functional assays demonstrate that loss of endothelial Jagged-1 does not perturb vascular/mesenchymal compartments. This work provides a comprehensive functional analysis of bone marrow niche components in determining how endothelial paracrine factors modulate hematopoietic stem cell function in an instructive manner.