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

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.

journal_name

Blood

journal_title

Blood

authors

Rafii S,Kloss CC,Butler JM,Ginsberg M,Gars E,Lis R,Zhan Q,Josipovic P,Ding BS,Xiang J,Elemento O,Zaninovic N,Rosenwaks Z,Sadelain M,Rafii JA,James D

doi

10.1182/blood-2012-07-444208

subject

Has Abstract

pub_date

2013-01-31 00:00:00

pages

770-80

issue

5

eissn

0006-4971

issn

1528-0020

pii

blood-2012-07-444208

journal_volume

121

pub_type

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