IntroductionThe existence of the hemangioblast has been proposed in the first decades of the 20th century. 1,2 It was suggested that the cells of the endothelial and hematopoetic lineages might derive from a common precursor, the hemangioblast, present in the blood islands of the yolk sac. Since then, many studies have contributed evidence that the hemangioblast might also be present in the postnatal life. Pelosi et al 3 showed that single CD34 ϩ KDR ϩ cells from adult BM or CB can generate both hematopoietic and endothelial cells in vitro and that these cells are endowed with long-term proliferative capacity. The potential of BM-derived hematopoietic stem cells to differentiate in vitro and in vivo into endothelial cells has been confirmed by other investigators. [4][5][6] This has also been confirmed in cancer models that allow cell tracing on the basis of cancer-specific genetic signature. For instance, Gunsilius et al 7 obtained in vitro endothelial cells that contained the Bcr/Abl fusion gene starting from blood or BM-derived MNCs of patients with chronic myelogeneous leukemia carrying the Bcr/Abl fusion gene, indicating that both endothelial and hematopietic lineages derive from a common progenitor. Similarly, hemangioblastic precursor cells that may contribute to maintaining both malignant hematopoiesis and angiogenesis have been suggested in other hematologic malignancies. 8,9 Importantly, the existence of BM-derived hematopoietic stem cells endowed with bilineage ability to reconstitute both hematopoietic and endothelial cells has been also confirmed at the single-cell level. 10 Moreover, transplanted vascular cells from adult thoracic aorta or inferior vena cava have been shown to contribute to the generation of hematopoietic cells in lethally irradiated recipients, 11 thus suggesting that bilineage development might reside in endothelial vessels, as well.Although the above-mentioned studies are convincing in supporting the existence of the hemangioblast in adult life, a precise identification of the hemangioblast with a clear-cut definition of characterizing molecular markers is still lacking. Several studies have shown an extensive overlap in the expression of hematopoietic and endothelial markers during early developmental stages, suggesting a close developmental relationship between the 2 lineages. In particular, markers such as CD34 and vascular endothelial growth factor receptor-2 (KDR), which are expressed on early progenitors of both lineages, are progressively down-regulated during hematopoietic differentiation but are conserved in fully differentiated endothelial cells. 12,13 In the present study, to possibly identify precursors in human adult peripheral blood (hPB) endowed with the hemangioblast developmental potentials, we established a new ex vivo long-term culture model aimed to support the differentiation of both the hematopoietic and endothelial lineages. By performing long-term-hematopoietic-endothelial cultures (LTC-HEs), we could identify from PB a cell population lacking the express...
A key mechanism responsible for processing of peptide-MHC class II complexes in mature Dendritic Cells (DCs) is the generalized activation of lysosomal function. Mechanisms underlie these developmental changes are controversial. Thus, it is unclear whether immature DCs can present self antigens, and which are the checkpoints that regulate antigen presentation in immature and mature DCs. Here we generated in-vitro human DCs from peripheral blood CD34+ hematopoietic stem cells (HSCs), by adding to the medium culture Flt-3, GM-CSF, IL-4, and TNF-a (cytokine cocktail, CC) at 37°C for 14 days, and analysed the lysosomal glycohydrolases production and function. Lysosomal enzymes, b-N-Acetyl-Hexosaminidase, a-Mannosidase, b-Galactosidase and b-Glucoronidase are highly increased in a wide range in DCs (14 days of culture) with respect to the CD34+HSCs. All the glycohydrolases activities measured at 3 and 7 days in-vitro culture, were similar and four times more than CD34+HSCs (day 0) respectively. Interestingly, no activities increase were observed, even when SCF, an early acting cytokine, promoting cellular proliferation, were added to the CC medium, indicating that this phenomenon is independent from the proliferation process. Moreover, LPS treatment, to induce DCs maturation, slightly enhance the specific activities of all enzymes that we tested as respect to the untreated cells. and support the evidence that the lysosomal glycohydrolases activation is up-stream to DCs maturation process. Furthermore, for the first time, this date indicated that lysosomal glycohydrolases are regulated during the stem cell differentiation process. Understanding the key mechanism leading this phenomenon is critical for therapeutic application in immunologic or neoplastic disease.
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