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Endothelium and NOTCH specify and amplify aorta-gonad-mesonephros-derived hematopoietic stem cells
- Source :
- Journal of Clinical Investigation. May, 2015, Vol. 125 Issue 5, p2032, 14 p.
- Publication Year :
- 2015
-
Abstract
- Hematopoietic stem cells (HSCs) first emerge during embryonic development within vessels such as the dorsal aorta of the aorta-gonad-mesonephros (AGM) region, suggesting that signals from the vascular microenvironment are critical for HSC development. Here, we demonstrated that AGM-derived endothelial cells (ECs) engineered to constitutively express AKT (AGM AKT-ECs) can provide an in vitro niche that recapitulates embryonic HSC specification and amplification. Specifically, nonengrafting embryonic precursors, including the VE-[cadherin.sup.-]expressing population that lacks hematopoietic surface markers, cocultured with AGM AKT-ECs specified into long-term, adult-engrafting HSCs, establishing that a vascular niche is sufficient to induce the endothelial-to-HSC transition in vitro. Subsequent to hematopoietic induction, coculture with AGM AKT-ECs also substantially increased the numbers of HSCs derived from VE-[cadherin.sup.+][CD45.sup.+] AGM hematopoietic cells, consistent with a role in supporting further HSC maturation and self-renewal. We also identified conditions that included NOTCH activation with an immobilized NOTCH ligand that were sufficient to amplify AGM-derived HSCs following their specification in the absence of AGM AKT-ECs. Together, these studies begin to define the critical niche components and resident signals required for HSC induction and self-renewal ex vivo, and thus provide insight for development of defined in vitro systems targeted toward HSC generation for therapeutic applications.<br />Introduction In the developing embryo, the earliest hematopoietic activity is characterized by lineage-restricted progenitors that arise initially in the yolk sac prior to and independent of hematopoietic stem cells (HSCs) [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 125
- Issue :
- 5
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.417895786
- Full Text :
- https://doi.org/10.1172/JCI80137