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Human ESC-derived hemogenic endothelial cells undergo distinct waves of endothelial to hematopoietic transition.

TitleHuman ESC-derived hemogenic endothelial cells undergo distinct waves of endothelial to hematopoietic transition.
Publication TypeJournal Article
Year of Publication2013
AuthorsRafii S, Kloss CC, Butler JM, Ginsberg M, Gars E, Lis R, Zhan Q, Josipovic P, Ding B-S, Xiang J, Elemento O, Zaninovic N, Rosenwaks Z, Sadelain M, Rafii JA, James D
JournalBlood
Volume121
Issue5
Pagination770-80
Date Published2013 Jan 31
ISSN1528-0020
KeywordsAntigens, CD, Cadherins, Cell Differentiation, Coculture Techniques, Embryonic Stem Cells, Endothelial Cells, Feeder Cells, Hematopoietic Stem Cells, Humans, Platelet Membrane Glycoprotein IIb, Transduction, Genetic
Abstract

UNLABELLED: Several studies have demonstrated that hematopoietic cells originate from endotheliumin early development; however, the phenotypic progression of progenitor cells during human embryonic hemogenesis is not well described. Here, we define the developmental hierarchy among intermediate populations of hematopoietic progenitor cells (HPCs) derived from human embryonic stem cells (hESCs). We genetically modified hESCs to specifically demarcate acquisition of vascular (VE-cadherin) and hematopoietic (CD41a) cell fate and used this dual-reporting transgenic hESC line to observe endothelial to hematopoietic transition by real-time confocal microscopy. Live imaging and clonal analyses revealed a temporal bias in commitment of HPCs that recapitulates discrete waves of lineage differentiation noted during mammalian hemogenesis. Specifically, HPCs isolated at later time points showed reduced capacity to form erythroid/ megakaryocytic cells and exhibited a tendency toward myeloid fate that was enabled by expression of the Notch ligand Dll4 on hESC-derived vascular feeder cells. These data provide a framework for defining HPC lineage potential, elucidate a molecular contribution from the vascular niche in promoting hematopoietic lineage progression, and distinguish unique subpopulations of hemogenic endothelium during hESC differentiation.

KEY POINTS: Live imaging of endothelial to hematopoietic conversion identifies distinct subpopulations of hESC-derived hemogenic endothelium. Expression of the Notch ligand DII4 on vascular ECs drives induction of myeloid fate from hESC-derived hematopoietic progenitors.

DOI10.1182/blood-2012-07-444208
Alternate JournalBlood
PubMed ID23169780
Grant List / / Howard Hughes Medical Institute / United States