A Tie2-Notch1 signaling axis regulates regeneration of the endothelial bone marrow niche

Abstract

Loss-of-function studies have determined that Notch signaling is essential for hematopoietic and endothelial development. By deleting a single allele of the Notch1 transcriptional activation domain we generated viable, post-natal mice exhibiting hypomorphic Notch signaling. These heterozygous mice, which lack only one copy of the transcriptional activation domain, appear normal and have no endothelial or hematopoietic phenotype, apart from an inherent, cell-autonomous defect in T-cell lineage development. Following chemotherapy, these hypomorphs exhibited severe pancytopenia, weight loss and morbidity. This phenotype was confirmed in an endothelial-specific, loss-of-function Notch1 model system. Ang1, secreted by hematopoietic progenitors after damage, activated endothelial Tie2 signaling, which in turn enhanced expression of Notch ligands and potentiated Notch1 receptor activation. In our heterozygous, hypomorphic model system, the mutant protein that lacks the Notch1 transcriptional activation domain accumulated in endothelial cells and interfered with optimal activity of the wildtype Notch1 transcriptional complex. Failure of the hypomorphic mutant to efficiently drive transcription of key gene targets such as Hes1 and Myc prolonged apoptosis and limited regeneration of the bone marrow niche. Thus, basal Notch1 signaling is sufficient for niche development, but robust Notch activity is required for regeneration of the bone marrow endothelial niche and hematopoietic recovery.

Notch signaling at the crossroads of innate and adaptive immunity

“…71 Moreover, mice transplanted with Notch1 hypomorphic hematopoietic stem cells displayed a cell-autonomous defect in T cell production that was associated with a decrease in BM lymphoid progenitors. 49 Most recently, a new mouse model allowing for temporal and hematopoietic-specific control of Rbpj expression and Notch responsiveness supported these findings, suggesting that lymphoid precursors first experience Notch signaling in the BM. 72 Nevertheless, Notch ligand expression and signaling intensity is tightly regulated to prevent extrathymic T cell development during steady-state conditions.…”

“…Indeed, Notch signaling between BM endothelial cells appeared necessary for niche regeneration and timely hematopoietic recovery after BM injury. 49 Thus, while Notch signaling may regulate the BM microenvironment, its cell-autonomous role in HSPCs remains debated. Unraveling Notch's critical role in T cell development began with the identification of a Notch activating mutation in human T-ALL with a rare t(7;9) chromosomal translocation.…”

“…Additionally, Notch signaling within the niche cell compartment per se may directly regulate stromal cell biology and thus subsequently affect both the innate and adaptive immune response. Given the role for Notch signaling during bone marrow endothelial cell regeneration, and the non-cell autonomous myeloproliferative disease following Rbpj inactivation in non-hematopoietic compartments, it is likely that Notch signaling between stromal niche cells also has functional consequences on innate and adaptive immune cells 48,49. New efforts are also needed to resolve the precise mechanisms underlying Notch as a transcription factor.…”

Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches

“…For example, HSCs produce VEGF-A and angiopoietin which induce vessel regeneration by stimulating Dll4-Notch signaling in type-H ECs for sprouting angiogenesis and vascular niche regeneration [ 218 , 249 ]. In addition, type-H ECs also release angiocrine factors and osteogenic factors which promote proliferation and differentiation of osteo-MSC-SCs in endosteal/arteriolar niches for vascularization and osteogenesis [ 218 , 221 , 249 , 266 , 268 – 275 ]. Thus, it is most likely the case that HSCs, MSC-SCs and EC-SCs are associated during differentiation and their progeny work together as niches for each other [ 276 ].…”

Molecular Modulation of Fetal Liver Hematopoietic Stem Cell Mobilization into Fetal Bone Marrow in Mice

“…Our data displayed that the recovery of the endothelial niche in Notch1 Δ /TAD mice was failed after chemotherapy and radiotherapy. We further proved that angiopoietin 1 activated Tie2 signaling, which results in Notch1 signaling activation and its target gene expression [ 47 ]. Mechanistically, loss of Notch1-TAD leads to the failure of properly assembling the Notch1/RBPJ/MAML trimolecular transcriptional complex, which results in decreased expression of Notch1 downstream targets, such as Hes1 and Dtx1 [ 46 , 48 ].…”