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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 Article has an altmetric score of 56

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 2

Long-term multilineage engraftment of vascular niche–induced MniPSC-MPP.

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Long-term multilineage engraftment of vascular niche–induced MniPSC-MPP....
Detection of primate CD45+ cells in blood of mice transplanted with EC-induced MniPSC-MPP, cytokine-induced MniPSC-MPP, or Mn BM CD34+ cells. (A) Kinetics of primate CD45+ cells in blood. *P < 0.05; **P < 0.005, Student’s t test. (B) Distinction between primate and mouse CD45+ cells by flow cytometry analysis. Middle panels: lymphoid and myeloid subset analysis. Right panels: flow cytometry plots showing CD3, CD20 single-positive and CD13, CD14 double-positive cells. (C) Primate CD45+ cells in BM. Dots indicate individual mice. Lines show mean/group. (D) Top panels: frequency of BM CFUs. M, macrophage; GM, granulocyte-macrophage; E, erythroid; GEMM, mixed. Bottom panels: colonies from BM of EC MniPSC-MPP mouse. Original magnification, ×4. Middle panels: Wright-stained macrophage and erythroid cells. Original magnification, ×20. Right panels: qRT-PCR for primate γ- and β-hemoglobin from erythroid (BFU-E) cells. Transcripts normalized to β-actin and calibrated to macaque blood (line indicates calibrator level). Transplantation studies were conducted in 8 to 12 mice/group over 3 independent experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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