CXCR4 Signaling Negatively Modulates the Bipotential State of Hemogenic Endothelial Cells Derived from Embryonic Stem Cells by Attenuating the Endothelial Potential

• Published in: Stem cells (Dayton, Ohio) Vol. 34; no. 12; pp. 2814 - 2824
• Main Authors: Ahmed, Tanzir, Tsuji‐Tamura, Kiyomi, Ogawa, Minetaro
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-12-2016
• Subjects: Animals; Antigens, CD - metabolism; Cadherins - metabolism; CD41 antigen; Cell Line; Cell Lineage; CXCL12 chemokine; CXCR4 receptor; Embryo, Mammalian - cytology; Embryos; Endothelial Cells - cytology; Endothelial Cells - metabolism; Hemangioblasts - cytology; Hemangioblasts - metabolism; Hematopoiesis; Hemogenic endothelial cells; Mice; Mice, Inbred ICR; Models, Biological; Mouse embryonic stem cells; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; Platelet Membrane Glycoprotein IIb - metabolism; Receptors, CXCR4 - metabolism; Signal Transduction; Stem cells; VE‐cadherin; CD41 antigen; CXCR4 receptor; CXCL12 chemokine; Mouse embryonic stem cells; VE-cadherin; Hemogenic endothelial cells
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2441

Hemogenic endothelial cells (HECs) are considered to be the origin of hematopoietic stem cells (HSCs). HECs have been identified in differentiating mouse embryonic stem cells (ESCs) as VE‐cadherin+ cells with both hematopoietic and endothelial potential in single cells. Although the bipotential state of HECs is a key to cell fate decision toward HSCs, the molecular basis of the regulation of the bipotential state has not been well understood. Here, we report that the CD41+ fraction of CD45‐ CD31+ VE‐cadherin+ endothelial cells (ECs) from mouse ESCs encompasses an enriched HEC population. The CD41+ ECs expressed Runx1, Tal1, Etv2, and Sox17, and contained progenitors for both ECs and hematopoietic cells (HCs) at a high frequency. Clonal analyses of cell differentiation confirmed that one out of five HC progenitors in the CD41+ ECs possessed the bipotential state that led also to EC colony formation. A phenotypically identical cell population was found in mouse embryos, although the potential was more biased to hematopoietic fate with rare bipotential progenitors. ESC‐derived bipotential HECs were further enriched in the CD41+ CXCR4+ subpopulation. Stimulation with CXCL12 during the generation of VE‐cadherin+ CXCR4+ cells attenuated the EC colony‐forming ability, thereby resulted in a decrease of bipotential progenitors in the CD41+ CXCR4+ subpopulation. Our results suggest that CXCL12/CXCR4 signaling negatively modulates the bipotential state of HECs independently of the hematopoietic fate. Identification of signaling molecules controlling the bipotential state is crucial to modulate the HEC differentiation and to induce HSCs from ESCs. Stem Cells 2016;34:2814–2824
ES cell‐derived CD45‐ VE‐cadherin+ CD41+ CXCR4+ cells represent a hemogenic endothelial cell (HEC) population. HECs encompass the differentiation programs for both the endothelial cell (EC) and hematopoietic cell (HC) lineages. A balance between these two programs provides an HEC with a bipotential state that allows the progeny of the cell to differentiate into both ECs and HCs. Fate of the bipotential HECs can be regulated by CXCL12/CXCR4 signaling, which suppresses the EC program independently of the hematopoietic fate.