Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells.

TitleVascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells.
Publication TypeJournal Article
Year of Publication2015
AuthorsGori JL, Butler JM, Chan Y-Y, Chandrasekaran D, Poulos MG, Ginsberg M, Nolan DJ, Elemento O, Wood BL, Adair JE, Rafii S, Kiem H-P
JournalJ Clin Invest
Volume125
Issue3
Pagination1243-54
Date Published2015 Mar 02
ISSN1558-8238
KeywordsAnimals, Cell Differentiation, Cells, Cultured, Coculture Techniques, Endothelial Cells, Endothelium, Vascular, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, Induced Pluripotent Stem Cells, Macaca nemestrina, Male, Mice, Inbred NOD, Mice, SCID, Multipotent Stem Cells, Stem Cell Niche
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.

DOI10.1172/JCI79328
Alternate JournalJ. Clin. Invest.
PubMed ID25664855
PubMed Central IDPMC4362238
Grant ListR01 HL084345 / HL / NHLBI NIH HHS / United States
P51 OD010425 / OD / NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
HL084345 / HL / NHLBI NIH HHS / United States
R01 HL115128 / HL / NHLBI NIH HHS / United States
P01 AI097100 / AI / NIAID NIH HHS / United States
R01 HL098489 / HL / NHLBI NIH HHS / United States
HL115128 / HL / NHLBI NIH HHS / United States
HL098489 / HL / NHLBI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 HL085693 / HL / NHLBI NIH HHS / United States
HL085693 / HL / NHLBI NIH HHS / United States