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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 - imaillar@pennmedicine.upenn.edu doi:10.3324/haematol.2019.230854
In the bone marrow, specialized non-hematopoietic cells form unique microenvironmental niches that support and regulate the functions of hematopoietic stem and progen- itor cells (HSPC).1 Although many niche factors are well defined, the role of Notch signaling remains controversial (see Figure 1). Notch signaling in HSPC has been reported to regulate hematopoietic stem cell maintenance, suppress myelopoiesis, and promote megakaryocyte/erythroid cell development.2-7 Mechanistically, most previous reports have been built on the concept that Notch receptors in HSPC interact with Notch ligands expressed in niche endothelial cells, or alternatively in other components of the bone mar- row (including other non-hematopoietic and hematopoietic cells) (Figure 1, and ). In contrast, several genetic models that inhibit all transcriptional effects of Notch signaling only in HSPC indicated that canonical Notch signaling is dispen- sable for HSPC maintenance, as well as myelo-erythro- poiesis, under both homeostatic and stress conditions.8,9 In this issue of Haematologica, Shao et al. bring a new perspec- tive to this debate: perhaps Notch signaling is critical for stress hematopoiesis, but indirectly so by promoting niche cell regeneration through Notch ligand-receptor interactions that remain confined to the bone marrow endothelium10 (Figure 1, ).
Unlike secreted niche factors, Notch signaling is a jux- tacrine communication pathway between signal-sending cells expressing agonistic Notch ligands (Dll1, Dll4, Jagged1, or Jagged2), and signal-receiving cells expressing Notch receptors (Notch1-4).11 Ligand-receptor interactions induce regulated proteolytic cleavage of the Notch receptor, releas- ing the Notch intracellular domain which is then free to translocate to the nucleus and alter gene transcription in sig- nal-receiving cells. Notch receptor and ligand expression has been reported in HSPC, osteoblasts, as well as key con- stituents of the perivascular niche, such as bone marrow endothelial cells.2,3,5,6,12,13 Because Notch ligands and receptors are expressed by a variety of hematopoietic and non- hematopoietic cells, defining specific interactions that are biologically and functionally relevant for the HSPC microen- vironment is a difficult task. For example, Notch signaling could be an important aspect of either endothelial- hematopoietic cell cross-talk (Figure 1, ), or communica- tion directly between endothelial niche cells (Figure 1, ). Likewise, tight control of Notch signaling between hematopoietic cells is essential, as de-repression of Dll4 in erythroblasts leads to premature differentiation of HSPC into T cells (Figure 1, ).14
Shao et al. provide compelling new data indicating that activation of Notch signaling between endothelial cells is a key component of HSPC niche restoration after bone mar- row injury. Hematopoietic cell recovery after chemotherapy
or radiation-induced myelosuppression relies heavily on
regeneration of the endothelial cell network in order to sup-
6,15,16
port the hematopoietic compartment. By examining the
role of Notch signaling after injury using bone marrow chimeras and genetic models of cell type-specific Notch inac- tivation, Shao et al. dissected the functional importance of two possible routes of communication: cross-talk between endothelial cells and HSPC (Figure 1, ), as well as Notch signaling between endothelial cells (Figure 1, ) that indi- rectly affects HSPC. First, the authors demonstrated that endothelial restoration after bone marrow injury relied on activation of Notch signaling through the Notch1 receptor. Myeloablative stress induced by chemotherapy or irradia- tion caused lethal pancytopenia in mice harboring a hypo- morphic Notch1 allele. This phenotype was linked to a reduc- tion in the number and frequency of HSPC after injury. Depletion of lymphoid-primed progenitors was also appar- ent. However, transplantation of Notch1 hypomorphic HSPC into wildtype hosts revealed that the hematopoietic recov- ery defect was extrinsic to HSPC. Moreover, ablation of the Notch1 receptor gene specifically in bone marrow endothelial cells using a tamoxifen-inducible VE-cadherin CreERT2 trans- gene recapitulated the pancytopenia, morbidity and hematopoietic failure observed after injury in Notch1 hypo- morphic mice. Together, these data suggest a role for Notch signaling during endothelial cell recovery. To further investi- gate this hypothesis, the authors found that Notch signaling was promptly activated in bone marrow endothelial cells after injury. Tie2 activation, which is critical for endothelial cell regeneration, appeared to enhance Notch signaling by inducing expression of both Notch receptors and ligands in bone marrow endothelial cells.16 Thus, Notch signals could be induced in bone marrow endothelial cells via a cross-talk involving expression of both Notch ligands and receptors in the endothelial compartment, with subsets of cells function- ing as signal-sending and others as signal-receiving cells (Figure 1, ) .
When considering the impact of Notch signaling in the bone marrow, it has often been assumed that the only func- tionally significant signals for hematopoiesis are mediated directly between niche cells and HSPC. However, it is also possible that non-cell-autonomous signals regulate HSPC function indirectly, while cell-autonomous Notch signals are dispensable. This concept has been entertained previously, as transplantation of wildtype bone marrow cells into recip- ient mice lacking the capacity to undergo Notch-driven sig- nals in the radioresistant host compartment led to altered hematopoietic differentiation, and eventually to myelopro- liferative disease.17 Likewise, Shao et al. highlight an often overlooked potential mechanism of HSPC regulation by showing that disruption of Notch signaling among endothe-
haematologica | 2019; 104(11)
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