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10.1172/JCI79328

http://scihub22266oqcxt.onion/10.1172/JCI79328
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C4362238!4362238!25664855
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suck abstract from ncbi


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pmid25664855      J+Clin+Invest 2015 ; 125 (3): 1243-54
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  • Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells #MMPMID25664855
  • Gori JL; Butler JM; Chan YY; Chandrasekaran D; Poulos MG; Ginsberg M; Nolan DJ; Elemento O; Wood BL; Adair JE; Rafii S; Kiem HP
  • J Clin Invest 2015[Mar]; 125 (3): 1243-54 PMID25664855show ga
  • Pluripotent stem cells (PSCs) represent an alternative hematopoietic stem cell (HSC) source for treating hematopoietic disease. The limited engraftment of human PSC?derived (hPSC-derived) multipotent progenitor cells (MPP) has hampered the clinical application of these cells and suggests that MPP require additional cues for definitive hematopoiesis. We hypothesized that the presence of a vascular niche that produces Notch ligands jagged-1 (JAG1) and delta-like ligand-4 (DLL4) drives definitive hematopoiesis. We differentiated hes2 human embryonic stem cells (hESC) and Macaca nemestrina?induced PSC (iPSC) line-7 with cytokines in the presence or absence of endothelial cells (ECs) that express JAG1 and DLL4. Cells cocultured with ECs generated substantially more CD34+CD45+ hematopoietic progenitors compared with cells cocultured without ECs or with ECs lacking JAG1 or DLL4. EC-induced cells exhibited Notch activation and expressed HSC-specific Notch targets RUNX1 and GATA2. EC-induced PSC-MPP engrafted at a markedly higher level in NOD/SCID/IL-2 receptor ? chain?null (NSG) mice compared with cytokine-induced cells, and low-dose chemotherapy-based selection further increased engraftment. Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction were similar to levels achieved for cord blood?derived MPP and up to 20-fold higher than those achieved with hPSC-derived MPP engraftment. Our findings indicate that endothelial Notch ligands promote PSC-definitive hematopoiesis and production of long-term engrafting CD34+ cells, suggesting these ligands are critical for HSC emergence.
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