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New Insights Into the Role of Notch Signaling in the Bone Marrow Ashley N EDITORIALS Notch in the niche: new insights into the role of Notch signaling in the bone marrow Ashley N. Vanderbeck1-3 and Ivan Maillard2-4 1VMD-PhD program at University of Pennsylvania School of Veterinary Medicine; 2Immunology Graduate Group, University of Pennsylvania; 3Abramson Family Cancer Research Institute, University of Pennsylvania and 4Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA E-mail: IVAN MAILLARD - [email protected] doi:10.3324/haematol.2019.230854 n the bone marrow, specialized non-hematopoietic cells or radiation-induced myelosuppression relies heavily on form unique microenvironmental niches that support and regeneration of the endothelial cell network in order to sup- regulate the functions of hematopoietic stem and progen- port the hematopoietic compartment.6,15,16 By examining the I 1 itor cells (HSPC). Although many niche factors are well role of Notch signaling after injury using bone marrow defined, the role of Notch signaling remains controversial chimeras and genetic models of cell type-specific Notch inac- (see Figure 1). Notch signaling in HSPC has been reported to tivation, Shao et al. dissected the functional importance of regulate hematopoietic stem cell maintenance, suppress two possible routes of communication: cross-talk between myelopoiesis, and promote megakaryocyte/erythroid cell endothelial cells and HSPC (Figure 1, ቢ), as well as Notch development.2-7 Mechanistically, most previous reports have signaling between endothelial cells (Figure 1, ባ) that indi- been built on the concept that Notch receptors in HSPC rectly affects HSPC. First, the authors demonstrated that interact with Notch ligands expressed in niche endothelial endothelial restoration after bone marrow injury relied on cells, or alternatively in other components of the bone mar- activation of Notch signaling through the Notch1 receptor. row (including other non-hematopoietic and hematopoietic Myeloablative stress induced by chemotherapy or irradia- cells) (Figure 1, ቢ and ቤ). In contrast, several genetic models tion caused lethal pancytopenia in mice harboring a hypo- that inhibit all transcriptional effects of Notch signaling only morphic Notch1 allele. This phenotype was linked to a reduc- in HSPC indicated that canonical Notch signaling is dispen- tion in the number and frequency of HSPC after injury. sable for HSPC maintenance, as well as myelo-erythro- Depletion of lymphoid-primed progenitors was also appar- poiesis, under both homeostatic and stress conditions.8,9 In ent. However, transplantation of Notch1 hypomorphic HSPC this issue of Haematologica, Shao et al. bring a new perspec- into wildtype hosts revealed that the hematopoietic recov- tive to this debate: perhaps Notch signaling is critical for ery defect was extrinsic to HSPC. Moreover, ablation of the stress hematopoiesis, but indirectly so by promoting niche Notch1 receptor gene specifically in bone marrow endothelial cell regeneration through Notch ligand-receptor interactions cells using a tamoxifen-inducible VE-cadherin CreERT2 trans- that remain confined to the bone marrow endothelium10 gene recapitulated the pancytopenia, morbidity and (Figure 1, ባ). hematopoietic failure observed after injury in Notch1 hypo- Unlike secreted niche factors, Notch signaling is a jux- morphic mice. Together, these data suggest a role for Notch tacrine communication pathway between signal-sending signaling during endothelial cell recovery. To further investi- cells expressing agonistic Notch ligands (Dll1, Dll4, Jagged1, gate this hypothesis, the authors found that Notch signaling or Jagged2), and signal-receiving cells expressing Notch was promptly activated in bone marrow endothelial cells receptors (Notch1-4).11 Ligand-receptor interactions induce after injury. Tie2 activation, which is critical for endothelial regulated proteolytic cleavage of the Notch receptor, releas- cell regeneration, appeared to enhance Notch signaling by ing the Notch intracellular domain which is then free to inducing expression of both Notch receptors and ligands in translocate to the nucleus and alter gene transcription in sig- bone marrow endothelial cells.16 Thus, Notch signals could nal-receiving cells. Notch receptor and ligand expression has be induced in bone marrow endothelial cells via a cross-talk been reported in HSPC, osteoblasts, as well as key con- involving expression of both Notch ligands and receptors in stituents of the perivascular niche, such as bone marrow the endothelial compartment, with subsets of cells function- endothelial cells.2,3,5,6,12,13 Because Notch ligands and receptors ing as signal-sending and others as signal-receiving cells are expressed by a variety of hematopoietic and non- (Figure 1, ባ) . hematopoietic cells, defining specific interactions that are When considering the impact of Notch signaling in the biologically and functionally relevant for the HSPC microen- bone marrow, it has often been assumed that the only func- vironment is a difficult task. For example, Notch signaling tionally significant signals for hematopoiesis are mediated could be an important aspect of either endothelial- directly between niche cells and HSPC. However, it is also hematopoietic cell cross-talk (Figure 1, ቢ), or communica- possible that non-cell-autonomous signals regulate HSPC tion directly between endothelial niche cells (Figure 1, ባ). function indirectly, while cell-autonomous Notch signals are Likewise, tight control of Notch signaling between dispensable. This concept has been entertained previously, hematopoietic cells is essential, as de-repression of Dll4 in as transplantation of wildtype bone marrow cells into recip- erythroblasts leads to premature differentiation of HSPC ient mice lacking the capacity to undergo Notch-driven sig- into T cells (Figure 1, ቤ).14 nals in the radioresistant host compartment led to altered Shao et al. provide compelling new data indicating that hematopoietic differentiation, and eventually to myelopro- activation of Notch signaling between endothelial cells is a liferative disease.17 Likewise, Shao et al. highlight an often key component of HSPC niche restoration after bone mar- overlooked potential mechanism of HSPC regulation by row injury. Hematopoietic cell recovery after chemotherapy showing that disruption of Notch signaling among endothe- haematologica | 2019; 104(11) 2117 Editorials Figure 1. Potential routes of Notch signaling in the bone marrow. Notch ligands and receptors are expressed by both non-hematopoietic and hematopoietic cellular elements in the bone marrow. Potential routes of Notch signaling that influence the function of hematopoietic stem and progenitor cells (HSPC) include: (ቢ) inter- action of Notch ligands in endothelial cells with Notch receptors in HSPC; (ባ) Notch ligand-receptor interactions between endothelial cells, with indirect effects on HSPC; (ቤ) interaction of Notch receptors in HSPC with Notch ligands expressed by other hematopoietic cells. In this issue, Shao et al. provide new data in support of Notch signaling within the endothelium (ባ) as a critical regulator of hematopoietic recovery after bone marrow injury. lial cells impaired hematopoietic recovery (Figure 1, ባ). actively engage Notch signaling. On the other hand, stalk While the authors identified Notch signaling as an cells undergo high levels of Notch signaling which essential component of the response to injury in the bone reduces expression of VEGFR2/3 and glycolytic enzymes, marrow, the mechanisms underlying Notch’s impact in ultimately helping to repress the tip cell fate while main- this context remain unclear. The bone marrow injury taining stalk cell identity.19 Thus, Notch activity may be response includes a complex interplay of signaling cues important during early stages of bone marrow vascula- secreted from multiple cellular sources. For example, ture reassembly by regulating pathways similar to VEGF-A, as well as Angiopoietin-1, are thought to control tip/stalk cell differentiation and by integrating angiogenic regeneration and reassembly of the bone marrow vascu- cues with the metabolic status of the endothelium. lature.15,16 Importantly, the cellular source, role and regula- Finally, it is possible that Notch acts through yet to be dis- tion of individual factors may differ markedly between covered mechanisms unique to the bone marrow vascu- steady-state conditions and after bone marrow injury.18 lature, whose regulation during steady-state conditions Shao et al. found that lack of Notch activation after injury and after injury remains only partially understood. increased apoptosis among endothelial cells, suggesting Notch signaling may also have roles in hematopoiesis that Notch functions as a pro-survival cue. During angio- beyond its functions in the HSPC niche. Dll4 inactivation genesis, Notch inhibits proliferation of endothelial cells in mesenchymal progenitor cells was reported to decrease and ultimately allows for proper formation of functional bone marrow common lymphoid progenitor numbers blood vessels.19 Thus, Notch signaling may restrict bone and impair thymopoiesis.12 Similarly, endothelial Dll4 marrow endothelial cell activation and entry into the cell inactivation was recently linked to decreased lymphoid cycle, ultimately protecting the endothelium from the progenitors and enhanced myelopoiesis.5 Consistent with DNA damage induced by chemotherapy and irradiation. these data, Shao et al. reported a cell-autonomous Alternatively,
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