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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2467-2481
Number of pages15
JournalCell reports
Volume23
Issue number8
DOIs
StatePublished - May 22 2018
Externally publishedYes

Bibliographical note

Funding Information:
We thank Matthew Raymond for editorial assistance. This work was supported by funds from the NIH ( R01HL116221 , U01HL099773 , U01HL134655 , and P51 RR000167 ), and The Charlotte Geyer Foundation .

Publisher Copyright:
© 2018 The Author(s)

Keywords

  • ETS1
  • hematopoiesis
  • hematopoietic stem cells
  • hemogenic endothelium
  • human pluripotent stem cells
  • MAPK/ERK signaling
  • T cells

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