Table 1.
References summarizing the experimental models to dissect the role of Notch signaling in stress hematopoiesis.
| Study model | Target cells | Notch target | Role/impact | References |
|---|---|---|---|---|
| NOTCH SIGNALING IN HSC MAINTENANCE, REGENERATION AND DIFFERENTIATION | ||||
| Mx1-cre; Notch1fl/fl | Hematopoietic cells and stromal cells | Not reported | Reduced thymus size and morphology; developmental arrest at double negative T cell stage; increased B cell numbers in thymus | Radtke et al., 1999 |
| Mx1-cre; RBPJfl/fl | Hematopoietic cells and stromal cells | Not reported | Block of T cell differentiation at the earliest stage with an increase of B cells in the thymus | Han et al., 2002 |
| OP9-DL1-HSC coculture; dnMAML1-HSC | Hematopoietic cells | Hes1, Pu.1, Fli1, Gata1 | OP9-DL1 promoted HSC differentiation into megakaryocytes; RBPJ/ICN/MAML Complex Mediates Megakaryocyte Development | Mercher et al., 2008 |
| Mx1-cre; RBPJfl/fl; Mx1-cre; Rosa26 dnMAML1 | Hematopoietic cells and stromal cells | Hes1, Dtx1 | Stable engraftment of dnMAML transduced HSCs; Reduction of T cell differentiation of the dnMAML transduced HSCs | Maillard et al., 2008 |
| Mx1-cre; RBPJ mice; Vav1-cre; RBPJ mice | Hematopoietic cells and stromal cells | Hes1, Hes5, Nrarp, Gata3 | Canonical Notch signaling is dispensable for all investigated stages of megakaryocyte, erythroid, and myeloid progenitors | Duarte et al., 2018 |
| Mx1-cre; Notch1fl/fl mice; Mx1-cre: Notch2fl/fl mice | Hematopoietic cells and stromal cells | Hes1 | Notch2 but not Notch1 inhibit HSC myeloid differentiation on immobilized Notch ligands; Notch2 but not Notch1 governs regeneration of LT-HSCs | Varnum-Finney et al., 2011 |
| VEcad-cre; Jag1fl/fl mice | Endothelial cells | Hes, Hey1 | Reduced LT-HSC number at steady state and during regeneration. Reduced HSC repopulating capacity in a competitive setting. Reduced Hes1 and Hey1 in HSCs after endothelial deletion of Jag1 | Poulos et al., 2013 |
| VEcad-cre; Jag2fl/fl mice | Endothelial cells | Hes, Hey1 | Unchanged LT-HSC number at steady state and reduced LT-HSC number during regeneration. Reduced capacity for Jag2ECKO mice HSCs to differentiate into T cells. Reduced Hey1 and increased Hes1 in HSCs after endothelial deletion of Jag2 | Guo et al., 2017 |
| Mx1-cre; RBPJfl/fl | Hematopoietic cells and stromal cells | miR-155 | Notch blocks HSC proliferation in a cell-autonomous manner; Notch in the BM microenvironment inhibit the onset of MPN disease via repressing NF-kB signaling | Wang L. et al., 2014 |
| RafVCC; Rbpjfl/fl mice RafVCC; Dll4fl/fl mice; RafVCC; Fbxw7 mice; RafVCC; NICD mice | Endothelial cells | Not reported | Enhanced Notch activity in endothelial cells increases the number of ephrin-B2+ ECs, Pdgfrb+ perivascular cells, cellular SCF levels and HSC cell number. Endothelial Notch reactivates HSC niches in aged mice | Kusumbe et al., 2016 |
| Vecad-cre; Notch1fl/fl mice; Notch1+/deltaTAD | Global or endothelial cells | Hes1, Myc, Hey1, Dtx1, pTa, EphrinB2, Dtx1 | Endothelial Notch1 activity promotes HSC regeneration by maintaining endothelial cell niche. Notch1 activity is required for CLP and T cell differentiation in a cell-autonomous manner | Shao et al., 2019 |
| Thymocytes overexpressing Lfng | Thymocytes | Not reported | Notch1 activity in early thymocytes functions to suppress B cell differentiation; Lfng inhibits Notch1 activity | Koch et al., 2001 |
| Bone marrow cell retroviral transduction of dnMAML | Hematopoietic cells | Not reported | dnMAML functions as a pan-Notch inhibitor. dnMAML inhibits T cell differentiation, promoted the emergence of B cells in thymus | Maillard et al., 2004 |
| Mx1-cre; Notch1fl/fl mice; Mx1-cre; Jag1fl/fl mice | Hematopoietic cells and stromal cells | Not reported | Deletion of Jag1 using Mx1-cre does not impact LT-HSC cell number at steady state or during regeneration; Mice with Jag1 and Notch1 deletion regenerate their HSC normally | Mancini et al., 2005 |
| dnMAML transduced human HSCs | Hematopoietic cells | Dtx1, Gata1 | Notch signaling is required for in vitro expansion of human HSCs and delays the onset of multipotent progenitor cells | Benveniste et al., 2014 |
| Notch1−/− mice; Notch2−/− mice | Global knockout mice | Not reported | Notch1 but not Notch2 is required for the emergence of HSC from hemogenic endothelium | Kumano et al., 2003 |
| Mx1-cre; Rosa26<stop>ICD fl/fl mice; Mx1-cre; Notch1fl/fl; Notch2fl/fl | Hematopoietic cells and stromal cells | Hes1, Gata3, Dtx1, Hey1, Nrap | Notch2 gain of function enhances erythroid differentiation; Notch1, Notch2 loss of function decreases stress erythropoiesis | Oh et al., 2013 |
| Vav1-cre; Ncstn fl/fl mice; Mx1-cre; Ncstn fl/fl mice; Mx1-cre; Ncstn fl/fl, N1IC mice | Hematopoietic cells and stromal cells | Not reported | Somatic Notch inactivation mutation was found in CMML patients. Deletion of gamma secretase component Ncstn lead to onset of CMML like disease and increase of myeloid gene signature in LKS cells | Klinakis et al., 2011 |
| Mx1-cre; Pofut1 mice | Hematopoietic cells and stromal cells | Not reported | Hematopoietic cell and niche Pofut1 both contributed to loss of T cells and myeloid hyperplasia | Yao et al., 2011 |
| MLL-AF9 Rosa wt/creERT2 mice; MLL-AF9, Rosa lsl-N2-IC/creERT2 mice; Ncstn−/−tet2−/− mice | All cells in mice | HES1, HEY1, NRARP; Bcl2, Adamdec1, Itgax, Mmp9, Cd74 | Notch is silenced in human AML samples; activation of Notch signaling lead to cell cycle arrest and apoptosis of AML cells; Combined Notch and Tet2 loss of function led to AML in mice | Lobry et al., 2013 |
| Retroviral mediated overexpression of Notch receptors or Hes1 | Human AML cells | Hes1 | Notch1, Notch2 or Hes1 overexpression in AML inhibits their growth and survival; Notch inhibitor dnMAML enhances in vivo AML engraftment | Kannan et al., 2013 |
| Immobilized Dll1 | Human CD34+ cells | Not reported | Immobilized Dll1 increase the number of ex vivo expanded human CD34+ cells that repopulate NOD-SCID mice | Ohishi et al., 2002 |
| Immobilized Dll1 | Human CD34+ cells | Not reported | Immobilized Dll1 increased the number of ex vivo expanded human CD34+ cells in the presence of cytokines SCF, Il6, Flt3, Il-11, and inhibited myeloid differentiation | Varnum-Finney et al., 2003 |
| Retroviral mediated overexpression of Hes1 | Human CD34+ cells | Not reported | Hes1 overexpression preserves purified HSCs in vitro and enriches side population HSC in vivo | Kunisato et al., 2003 |
| Immobilized Dll4 | Human CD34+ cells | Not reported | Membrane-bound Delta-4 Notch ligand reduces the proliferative activity of primitive human hematopoietic CD34+ CD38low cells while maintaining their long term colony-initiating cell potential | Lauret et al., 2004 |
| Immobilized Dll4 | Human CD34+ cells | E2F4, Rb | The Notch Delta-4 ligand helps to maintain the quiescence and the short-term reconstitutive potential of hematopoietic progenitor cells | Catelain et al., 2014 |
| Immobilized Dll1 | Human CD34+ cells | Not reported | Immobilized Dll1 increased the number of expanded human CD34+ cells and results in engraftment and rapid myeloid reconstitution | Delaney et al., 2010 |
| Endothelial-HSC coculture, Mx1-cre; Notch1, Notch2 mice | Mouse HSCs | Hes1 | Endothelial cell promote the expansion of LT-HSCs. Notch signaling is required for efficient HSC expansion | Butler et al., 2010 |
| Bone marrow stromal cells overexpressing Dll1-HSC coculture | Mouse HSCs | Not reported | Bone marrow stromal cells overexpressing Dll1 inhibits B cell differentiation and promotes T cells | Schmitt and Zúñiga-Pflücker, 2002 |
| OP9-DL1-HSC coculture | Mouse HSCs | Not reported | Notch signaling is required for T cell differentiation at DN1 and DN2 stage. The fate decision between T cell and B cell happens before double negative stage | Schmitt et al., 2004 |
| OP9-DL1-HSC coculture | Human CD34+ cells | Not reported | OP9 cells overexpressing Dll1 promote the differentiation of human CD34+ cells into T cells that can be activated in vitro | Motte-Mohs et al., 2005 |
| Mouse Fibroblast overexpressing Dll4; human fibroblast overexpressing Dll4 | Human CD34+ cells | Not reported | Mouse fibroblast, but not human fibroblast or NIH3T3 cells overexpressing Dll4 promote efficient differentiation of human CD34+ cells into T cells | Mohtashami et al., 2013 |
| OP9-Dll1-HSC coculture; OP9-Dll4-HSC coculture | Mouse HSCs | Dtx1, Nrarp, Gata3 | Dll4 maintains its ability to repress B cells and promote T cell differentiation even at lower dose | Mohtashami et al., 2010 |
| OP9-Jag2-HSC coculture | Human CD34+ cells | Hes1, Dtx1, Nrarp, Notch3, Gata3, Tcf7 | Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions to favor T cell differentiation | Walle et al., 2011 |
| Mx1-cre; RBPJfl/fl mice | Hematopoietic cells and stromal cells | Not reported | RBPJ disruption leads to increased mortality and sensitivity to total body irradiation. Mouse Dll1 infusion increased the myeloid cell numbers during regeneration | Chen et al., 2016 |
| RafVCC; Dll4fl/fl mice; RafVCC; Dll1f/fl mice | Endothelial cells | Not reported | Reduction of Dll1 and Dll4 expression in BM endothelial cells following stress; endothelial Dll4 deletion did not reduce LT-HSC cell number but lead to myeloid skewing of LT-HSCs | Tikhonova et al., 2019 |
| Nod-scid mice with T-ALL xenografts | N/A | Not reported | Endothelial cell expression of Dll4 correlated with increased tumor proliferation. Inhibiting Dll4 lead to tumor dormancy | Indraccolo et al., 2009 |
| Anti-Notch neutralizing antibodies | B-ALL | Not reported | Notch3/4 signaling and Jagged1/2, Dll1 promote the survival of B-ALL cells | Kamdje and Krampera, 2011 |
| Neutralizing antibodies for Dll4, Notch1, Notch2/3 | T-ALL | Dtx1, Hes1 | Dll4 is expressed in the microenvironment of NOD-SCID mice bearing T-ALL. Blocking Dll4 induces T-ALL death | Minuzzo et al., 2015 |
| MMTV-cre; Mib1fl/fl mice; Mx1-cre; Mib1fl/fl mice | Hematopoietic cells and stromal cells | Not reported | Defective Notch activation in microenvironment leads to myeloproliferative disease | Kim et al., 2008 |
| siRNA mediated reduction of Notch1 in endothelial cells; Vecad-cre, Notch+/− mice | Endothelial cells | Hes1, Heyl | Endothelial NOTCH1 is suppressed by circulating lipids and antagonizes inflammation during atherosclerosis | Briot et al., 2015 |
| Vecad-cre, Notch+/− mice; human endothelial cell under shear stress | Endothelial cells | Not reported | NOTCH1 is atheroprotective and acts as a mechanosensor in adult arteries | Mack et al., 2017 |
| ApoE/; RBPJflox/flox; Cdh5-CreERT | Endothelial cells | Hes1, Vcam1, Icam1, Nfkbia, Myd88 | Endothelial Jag1-RBPJ signaling promotes inflammatory leucocyte recruitment and atherosclerosis | Nus et al., 2016 |
| ICN1-T-ALL mice | Osteoblast cells | Dtx1, Hes1, Hey1, Notch2 | Stromal Notch activation in ICN1 T-ALL marrow leads to suppression of osteoblastic cells and their HSC supporting functions | Wang et al., 2016 |