Notch signaling regulates multiple cell fate decisions by hematopoietic precursors. To address whether different amounts of Notch ligand influence lineage choices, we cultured murine bone marrow lin−Sca-1+c-kit+ cells with increasing densities of immobilized Delta1ext-IgG consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG1. We found that relatively lower densities of Delta1ext-IgG enhanced the generation of Sca-1+c-kit+ cells, Thy1+CD25+ early T cell precursors, and B220+CD43−/lo cells that, when cocultured with OP9 stroma cells, differentiated into CD19+ early B cell precursors. Higher densities of Delta1ext-IgG also enhanced the generation of Sca-1+c-kit+ precursor cells and promoted the development of Thy1+CD25+ cells, but inhibited the development of B220+CD43−/lo cells. Analyses of further isolated precursor populations suggested that the enhanced generation of T and B cell precursors resulted from the effects on multipotent rather than lymphoid-committed precursors. The results demonstrate the density-dependent effects of Delta1 on fate decisions of hematopoietic precursors at multiple maturational stages and substantiate the previously unrecognized ability of Delta1 to enhance the development of both early B and T precursor cells.

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IntroductionHepatic stellate cells reside within the perisinusoidal space of Disse beneath the endothelial barrier and undergo a gradual transition from a quiescent, vitamin A-storing phenotype to an activated myofibroblast-like phenotype after liver injury. [1][2][3][4][5] These activated stellate cells synthesize large amounts of extracellular matrix proteins, such as collagens I, III, IV, V, and VI, fibronectin, laminin, and proteoglycans, during liver fibrogenesis. [6][7][8] Hepatic stellate cells have long cytoplasmic processes that run parallel to the sinusoidal endothelial wall, make contact with numerous hepatocytes, and function as liver-specific pericytes. 4,9,10 As hepatic stellate cells contract and relax in response to various vasoactive mediators, they may play a role in the regulation of sinusoidal tone and blood flow in normal liver. 10,11 Accordingly, hepatic stellate cells are associated with liver fibrosis and portal hypertension. However, the exact nature and origin of hepatic stellate cells have not been fully elucidated, despite the pathophysiologic implications.Hepatic stellate cells express mesenchymal markers, such as vimentin, desmin, and ␣-smooth muscle actin (␣-SMA), or neural/ neuroectodermal markers, such as glial fibrillary acidic protein (GFAP), neural cell adhesion molecule, and synaptophysin. 2,5,[12][13][14][15][16] Based on these characteristic phenotypes, the embryonic origin of hepatic stellate cells is thought to be the septum transversum mesenchyme or neural crest. 2,17,18 Cassiman et al 19 reported that hepatic stellate cells do not descend from the neural crest in transgenic mice expressing yellow fluorescent protein in all neural crest cells and their derivatives, and they may derive from the septum transversum mesenchyme, endoderm, or the mesothelial liver capsule. On the other hand, the origin of hepatic stellate cells in the adult liver has remained obscure.Recently, some investigators have demonstrated that crude bone marrow (BM) cells can populate the hepatic stellate cells of lethally irradiated mice. 20,21 Because adult BM contains both hematopoietic stem cells and mesenchymal stem cells, it is unclear which type of stem cell truly contributes to hepatic stellate cells. Previous reports revealed that glomerular mesangial cells in kidney and perivascular pericyte-like cells in brain are derived from hematopoietic stem cells in mice that received single hematopoietic stem-cell transplants. 22,23 Interestingly, both cell types are considered to belong to the myofibroblast family. More recently, it has also been reported that fibroblasts and myofibroblasts in many organs and tissues originate from hematopoietic stem cells. 24 From the observation that myofibroblasts are of hematopoietic stem-cell origin and the notion that the quiescent hepatic stellate cells switch to activated myofibroblast-like cells in association with inflammation, we hypothesized that hepatic stellate cells may also be derived from hematopoietic stem cells.To test our hypothesis, we generated c...

Clinical and histopathological features were investigated in 43 cases of oral lobular capillary hemangiomas (LCH) with a special reference to characteristics of the vascular elements. The lesions affected females more than males by a ratio of 1:1.5. Average age of the patients was 52.7 years. The lesions involved the gingiva (n = 15), the tongue (n = 13), the labial mucosa (n = 10) and other sites. The lesions appeared usually as a pedunculated mass with ulceration; size of the lesions was up to 15 mm. Histologically, a lobular area and an ulcerative area were distinguished. The density of vessels was about 1045/mm2 and 160/mm2 in the lobular and ulcerative areas, respectively. The average diameter of the vascular lumen was 9.1 5.6 mm (range: 2.8-42.0 mm) and 18.8 20.9 mm (range: 5.6-139.7 mm) in the lobular and ulcerative areas, respectively. In the lobular area, most of the vessels had an inner layer of endothelial cells showing positive reaction for von Willebrand factor (vWF) and CD34, as well as an outer layer of mesenchymal cells showing positive reaction for alpha-smooth muscle actin (ASMA). However, in the ulcerative area, there was a variety of types of vessels consisting of various proportions of both endothelial and ASMA-positive perivascular mesenchymal cells. These results indicate that most of the vascular elements in the lobular area resemble more pericapillary microvascular segments than they do capillaries. Thus, the authors propose the term 'lobular pericapillary hemangioma' to represent this type of lesion.

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