Notch/Delta4 Interaction in Human Embryonic Liver CD34 super(+) CD38 super(-) Cells: Positive Influence on BFU-E Production and LTC-IC Potential Maintenance

• Published in: Stem cells (Dayton, Ohio) Ohio), 2005-04, Vol.23 (4), p.550-560
• Main Authors: Dando, Jonathan S, Tavian, Manuela, Catelain, Cyril, Poirault, Sonia, Bennaceur-Griscelli, Annelise, Sainteny, Francoise, Vainchenker, William, Peault, Bruno, Lauret, Evelyne
• Format: Article
• Language: English
• ISSN: 1066-5099

We investigated whether Notch signaling pathways have a role in human developmental hematopoiesis. In situ histochemistry analysis revealed that Notch1, 2, and 4 and Notch ligand (Delta1-4, and Jagged1) proteins were not expressed in the yolk sac blood islands, the para-aortic splanchnopleure, the hematopoietic aortic clusters, and at the early stages of embryonic liver hematopoiesis. Notch1-2, and Delta4 were eventually detected in the embryonic liver, from 34 until 38 days postconception. Fluorescence-activated cell sorter analysis showed that first-trimester embryonic liver CD34 super(+)CD38 super(low) cells expressed both Notch1 and Notch2. When these cells were cultured on S17 stroma stably expressing Delta4, a 2.6-fold increase in BFU-E number was observed at day 7, as compared with cultures with control stroma, and this effect was maintained for 2 weeks. Importantly, exposure of these cells to Delta4 under these conditions maintained the original frequency and quality of long-term culture-initiating cells (LTC-ICs), while control cultures quickly resulted in the extinction of this LTC-IC potential. Furthermore, short-term exposure of embryonic liver adherent cells to erythropoietin resulted in a dose-dependent increase in Delta4 expression, almost doubling the expression observed with untreated stroma. This suggests that Delta4 has a role in the regulation of hematopoiesis after a hypoxic stress in the fetus.