SOX17 integrates HOXA and arterial programs in hemogenic endothelium to drive definitive lympho-myeloid hematopoiesis

Ho Sun Jung; Gene Uenishi; Mi Ae Park; Peng Liu; Kran Suknuntha; Matthew Raymond; Yoon Jung Choi; James A Thomson; Irene M Ong; Igor I Slukvin

doi:10.1016/j.celrep.2021.108758

SOX17 integrates HOXA and arterial programs in hemogenic endothelium to drive definitive lympho-myeloid hematopoiesis

Cell Rep. 2021 Feb 16;34(7):108758. doi: 10.1016/j.celrep.2021.108758.

Authors

Affiliations

¹ Wisconsin National Primate Research Center, University of Wisconsin Graduate School, 1220 Capitol Court, Madison, WI 53715, USA.
² Departments of Statistics and of Biostatistics and Medical Informatics, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
³ Chakri Naruebodindra Medical Institute, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Samut Prakan 10540, Thailand; Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, 600 Highland Avenue, Madison, WI 53792, USA.
⁴ 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, Santa Barbara, CA 93106, USA.
⁵ Wisconsin National Primate Research Center, University of Wisconsin Graduate School, 1220 Capitol Court, Madison, WI 53715, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, 600 Highland Avenue, Madison, WI 53792, USA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53707-7365, USA. Electronic address: islukvin@wisc.edu.

Abstract

SOX17 has been implicated in arterial specification and the maintenance of hematopoietic stem cells (HSCs) in the murine embryo. However, knowledge about molecular pathways and stage-specific effects of SOX17 in humans remains limited. Here, using SOX17-knockout and SOX17-inducible human pluripotent stem cells (hPSCs), paired with molecular profiling studies, we reveal that SOX17 is a master regulator of HOXA and arterial programs in hemogenic endothelium (HE) and is required for the specification of HE with robust lympho-myeloid potential and DLL4⁺CXCR4⁺ phenotype resembling arterial HE at the sites of HSC emergence. Along with the activation of NOTCH signaling, SOX17 directly activates CDX2 expression, leading to the upregulation of the HOXA cluster genes. Since deficiencies in HOXA and NOTCH signaling contribute to the impaired in vivo engraftment of hPSC-derived hematopoietic cells, the identification of SOX17 as a key regulator linking arterial and HOXA programs in HE may help to program HSC fate from hPSCs.

Keywords: CDX2; HOXA; NOTCH signaling; SOX17; arterial hemogenic endothelium; hematopietic development; hemogenic endothleium specification; human pluripotent stem cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / physiology
Embryonic Stem Cells / cytology
Embryonic Stem Cells / metabolism
Hematopoiesis / genetics*
Homeodomain Proteins / metabolism*
Humans
Induced Pluripotent Stem Cells / cytology
Induced Pluripotent Stem Cells / metabolism
SOXF Transcription Factors / metabolism*

Substances

Homeodomain Proteins
SOX17 protein, human
SOXF Transcription Factors
HoxA protein

Abstract

Publication types

MeSH terms

Substances

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