Adenosine signaling promotes hematopoietic stem and progenitor cell emergence.
Bottom Line: A2b adenosine receptor activation induced CXCL8 via cAMP-protein kinase A (PKA) and mediated hematopoiesis.We further show that adenosine increased multipotent progenitors in a mouse embryonic stem cell colony-forming assay and in embryonic day 10.5 aorta-gonad-mesonephros explants.Our results demonstrate that adenosine signaling plays an evolutionary conserved role in the first steps of HSPC formation in vertebrates.
Affiliation: Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02115 Harvard Stem Cell Institute, Howard Hughes Medical Institute, and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.Show MeSH
Related in: MedlinePlus
License 1 - License 2
Mentions: The abortive EHT of flk1:GFP cells could result from a lack of hemogenic potential in these cells. We then examined whether adenosine regulates HE specification, the onset of EHT. The master hematopoietic transcriptional regulator scl is critical for establishing the hematopoietic potential in aorta endothelial cells and plays its role before runx1 during definitive hematopoiesis. In zebrafish, an N-terminal truncated scl-β isoform is essential for HSPC emergence. The scl reporter line Tg(sclβ:d2eGFP) marks the hemogenic vascular endothelium, which is later transformed to HSPCs via EHT (Zhen et al., 2013). We altered adenosine signaling in Tg(sclβ:d2eGFP) embryos. In the absence of A2b, scl-β:GFP+ HE cell population was strongly reduced (1.6 ± 0.2/somite vs. 3.5 ± 0.3/somite [con]; Fig. 6, A–B′ and H). Addition of A2b receptor agonist BAY 60-6583 to wild-type embryos increased the number of scl-β:GFP+ in the AGM (4.6 ± 0.7/somite vs. 3.5 ± 0.5/somite [con]; Fig. 6, C, C′, and H). Overexpression of scl mRNA in zebrafish embryos partially rescued runx1+/cmyb+ HSPCs in A2b-deficient embryos (Fig. 6, D–G and I). These results indicate that adenosine signaling mediates scl+ hemogenic vascular endothelium. Together, our data suggest that adenosine mediates HSPC formation via regulation of hematopoietic commitment of endothelial cells.
Affiliation: Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02115 Harvard Stem Cell Institute, Howard Hughes Medical Institute, and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.