Notch/Delta4 interaction in human embryonic liver CD34+ CD38- cells: positive influence on BFU-E production and LTC-IC potential maintenance.
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(+)CD38(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.
Dando
Jonathan S
JS
U362 Inserm, Institut Gustave Roussy, PR1, 94800 Villejuif, France.
Tavian
Manuela
M
Catelain
Cyril
C
Poirault
Sonia
S
Bennaceur-Griscelli
Annelise
A
Sainteny
Françoise
F
Vainchenker
William
W
Péault
Bruno
B
Lauret
Evelyne
E
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34 / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D002448:Cell Adhesion; D002460:Cell Line; D018920:Coculture Techniques; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism; D005434:Flow Cytometry; D006410:Hematopoiesis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008099:Liver / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; D001798:Blood Proteins; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch; D004921:Erythropoietin; D051997:ADP-ribosyl Cyclase 1