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Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells
Jennifer L. Gori, … , Shahin Rafii, Hans-Peter Kiem
Jennifer L. Gori, … , Shahin Rafii, Hans-Peter Kiem
Published February 9, 2015
Citation Information: J Clin Invest. 2015;125(3):1243-1254. https://doi.org/10.1172/JCI79328.
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Technical Advance Stem cells

Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells

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Abstract

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 γ 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.

Authors

Jennifer L. Gori, Jason M. Butler, Yan-Yi Chan, Devikha Chandrasekaran, Michael G. Poulos, Michael Ginsberg, Daniel J. Nolan, Olivier Elemento, Brent L. Wood, Jennifer E. Adair, Shahin Rafii, Hans-Peter Kiem

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Figure 3

hESCs differentiated in a vascular niche give rise to engrafting MPP with in vivo myeloid and lymphoid potential.

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hESCs differentiated in a vascular niche give rise to engrafting MPP wit...
(A) Kinetics of EC-induced hes2-MPP engraftment compared with mice transplanted with ECs alone. (B) Distinction between the human and mouse CD45. (C) Th1 cytokine production by human CD3+ cells and CD14+ cells. For cytokine assays, cells were isolated from organs of 3 mice/group (3 biological replicates) and 3 technical replicates were run for each test.
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