Notch Receptor-Ligand Engagement Maintains Hematopoietic Stem Cell Quiescence and Niche Retention

Abstract

Notch is long recognized as a signaling molecule important for stem cell self-renewal and fate determination. Here we reveal a novel adhesive role of Notch-ligand engagement in hematopoietic stem and progenitor cells (HSPCs). Using mice with conditional loss of O-fucosylglycans on Notch EGF-like repeats important for the binding of Notch ligands, we report that HSPCs with faulty ligand binding ability display enhanced cycling accompanied by increased egress from the marrow, a phenotype mainly attributed to their reduced adhesion to Notch ligand-expressing stromal cells and osteoblastic cells and their altered occupation in osteoblastic niches. Adhesion to Notch ligand-bearing osteoblastic or stromal cells inhibits wild type but not O-fucosylglycan-deficient HSPC cycling, independent of RBP-JK-mediated canonical Notch signaling. Furthermore, Notch-ligand neutralizing antibodies induce RBP-JK-independent HSPC egress and enhanced HSPC mobilization. We therefore conclude that Notch receptor-ligand engagement controls HSPC quiescence and retention in the marrow niche that is dependent on O-fucosylglycans on Notch.

Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function

“…Isolation of HSPCs, analysis of megakaryocyte/erythroid progenitors and Ki67 staining were performed as described (22). Osteoblast sorting and cell surface CXCL12 staining were performed using a modified procedure (22, 23).…”

“…Osteoblast sorting and cell surface CXCL12 staining were performed using a modified procedure (22, 23). Megakaryocyte progenitors and erythroid progenitor markers were analyzed by PE-anti-CD41, PE-anti-TER119, and APC-anti-CD71 of LSK cells.…”

Cell cycle regulation of hematopoietic stem or progenitor cells

“…As an example of one mechanism responsible for this effect, Bernstein et al showed that the Notch transmembrane receptors on HSCs were activated by their ligands (Jagged 1 or Jagged 2) on stromal cells, promoting self-renewal of HSCs [98]. A recent study showed that Notch receptor ligand engagement maintains hematopoietic stem cell quiescence and niche retention [99].…”

Protein O-Glucosyltransferase 1 (POGLUT1) Promotes Mouse Gastrulation through Modification of the Apical Polarity Protein CRUMBS2

“…The biological importance of this type of protein modification is highlighted by dozens of human diseases caused by congenital disorders of glycosylation (CDGs), which are categorized based the chemical linkage, the added sugar, and the enzymes mutated in affected individuals [ 8 – 10 ]. Developmental defects in mice with mutations in glycosyltransferases have defined specific developmental roles for protein glycosylation in FGF and Notch signaling and in the composition of the extracellular matrix [ 11 – 18 ].…”