title: Role of SOX17 in hematopoietic development from human embryonic stem cells.
abstract: To search for genes that promote hematopoietic development from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), we overexpressed several known hematopoietic regulator genes in hESC/iPSC-derived CD34(+)CD43(-) endothelial cells (ECs) enriched in hemogenic endothelium (HE). Among the genes tested, only Sox17, a gene encoding a transcription factor of the SOX family, promoted cell growth and supported expansion of CD34(+)CD43(+)CD45(-/low) cells expressing the HE marker VE-cadherin. SOX17 was expressed at high levels in CD34(+)CD43(-) ECs compared with low levels in CD34(+)CD43(+)CD45(-) pre-hematopoietic progenitor cells (pre-HPCs) and CD34(+)CD43(+)CD45(+) HPCs. Sox17-overexpressing cells formed semiadherent cell aggregates and generated few hematopoietic progenies. However, they retained hemogenic potential and gave rise to hematopoietic progenies on inactivation of Sox17. Global gene-expression analyses revealed that the CD34(+)CD43(+)CD45(-/low) cells expanded on overexpression of Sox17 are HE-like cells developmentally placed between ECs and pre-HPCs. Sox17 overexpression also reprogrammed both pre-HPCs and HPCs into HE-like cells. Genome-wide mapping of Sox17-binding sites revealed that Sox17 activates the transcription of key regulator genes for vasculogenesis, hematopoiesis, and erythrocyte differentiation directly. Depletion of SOX17 in CD34(+)CD43(-) ECs severely compromised their hemogenic activity. These findings suggest that SOX17 plays a key role in priming hemogenic potential in ECs, thereby regulating hematopoietic development from hESCs/iPSCs.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Nakajima-Takagi
authors.forename: Mitsujiro
authors.initials: M
authors.lastname: Osawa
authors.forename: Motohiko
authors.initials: M
authors.lastname: Oshima
authors.forename: Haruna
authors.initials: H
authors.lastname: Takagi
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyagi
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Endoh
authors.forename: Takaho A
authors.initials: TA
authors.lastname: Endo
authors.forename: Naoya
authors.initials: N
authors.lastname: Takayama
authors.forename: Koji
authors.initials: K
authors.lastname: Eto
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Toyoda
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D005312:Fetal Blood / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D055760:SOXF Transcription Factors / Q000235:genetics* / Q000502:physiology*; D014161:Transduction, Genetic / Q000379:methods
chemical_list: D011993:Recombinant Fusion Proteins; C109188:SOX17 protein, human; D055760:SOXF Transcription Factors