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

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Abstract
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+CD38low 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.