Activation of the Arterial Program Drives Development of Definitive Hemogenic Endothelium with Lymphoid Potential

Mi Ae Park; Akhilesh Kumar; Ho Sun Jung; Gene Uenishi; Oleg V. Moskvin; James A. Thomson; Igor I. Slukvin

Cell Reports (May 2018)

Activation of the Arterial Program Drives Development of Definitive Hemogenic Endothelium with Lymphoid Potential

Mi Ae Park,
Akhilesh Kumar,
Ho Sun Jung,
Gene Uenishi,
Oleg V. Moskvin,
James A. Thomson,
Igor I. Slukvin

Affiliations

Mi Ae Park: National Primate Research Center, University of Wisconsin Graduate School, 1220 Capitol Court, Madison, WI 53715, USA
Akhilesh Kumar: National Primate Research Center, University of Wisconsin Graduate School, 1220 Capitol Court, Madison, WI 53715, USA
Ho Sun Jung: National Primate Research Center, University of Wisconsin Graduate School, 1220 Capitol Court, Madison, WI 53715, USA
Gene Uenishi: National Primate Research Center, University of Wisconsin Graduate School, 1220 Capitol Court, Madison, WI 53715, USA
Oleg V. Moskvin: National Primate Research Center, University of Wisconsin Graduate School, 1220 Capitol Court, Madison, WI 53715, USA
James A. Thomson: Morgridge Institute for Research, 330 N. Orchard Street, Madison, WI 53715, USA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53707-7365, USA; Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106, USA
Igor I. Slukvin: National Primate Research Center, University of Wisconsin Graduate School, 1220 Capitol Court, Madison, WI 53715, USA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53707-7365, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, 600 Highland Avenue, Madison, WI 53792, USA; Corresponding author

Journal volume & issue: Vol. 23, no. 8
pp. 2467 – 2481

Abstract

Read online

Summary: Understanding the pathways guiding the development of definitive hematopoiesis with lymphoid potential is essential for advancing human pluripotent stem cell (hPSC) technologies for the treatment of blood diseases and immunotherapies. In the embryo, lymphoid progenitors and hematopoietic stem cells (HSCs) arise from hemogenic endothelium (HE) lining arteries but not veins. Here, we show that activation of the arterial program through ETS1 overexpression or by modulating MAPK/ERK signaling pathways at the mesodermal stage of development dramatically enhanced the formation of arterial-type HE expressing DLL4 and CXCR4. Blood cells generated from arterial HE were more than 100-fold enriched in T cell precursor frequency and possessed the capacity to produce B lymphocytes and red blood cells expressing high levels of BCL11a and β-globin. Together, these findings provide an innovative strategy to aid in the generation of definitive lymphomyeloid progenitors and lymphoid cells from hPSCs for immunotherapy through enhancing arterial programming of HE. : Park et al. find that activation of the arterial program through ETS1 overexpression or by modulating MAPK/ERK signaling pathways at the mesodermal stage of development dramatically enhances formation of arterial-type hemogenic endothelium (HE) from hPSCs. Blood cells generated from arterial HE are highly enriched in definitive lymphomyeloid progenitors. Keywords: human pluripotent stem cells, hemogenic endothelium, T cells, hematopoietic stem cells, hematopoiesis, ETS1, MAPK/ERK signaling

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal