title: Twist-1, a novel regulator of hematopoietic stem cell self-renewal and myeloid lineage development.
abstract: Transcription factor Twist-1 plays essential roles in specification and differentiation of mesoderm-derived tissues. Growing evidences now link Twist-1 to the acquisition of stem-cell-like properties. However, the role of Twist-1 in hematopoietic stem cell (HSC) remains largely uncharacterized. We report that Twist-1 is more highly expressed in murine HSC and its expression declines with differentiation. To investigate Twist-1 gene function, retroviral-mediated overexpression or removal experiments are performed. Competitive repopulation studies demonstrate that enforced expression of Twist-1 in HSC-enriched Lin(-) c-Kit(+) Sca-1(+) (LKS) cells results in an increase in the size of the G(0) population, and in their reconstitution ability after the first and a second transplantation. Conversely, removal of Twist-1 in LKS cells impairs their ability to repopulate. In addition, increased Twist-1 expression causes a shift toward production of myeloid cells. Twist-1 transduction in LKS cells activates myeloid lineage-determining factors PU.1 and GATA-1 and downregulates lymphoid factor GATA-3 in vitro, suggesting that Twist-1-mediated myeloid skewing occurs in hematopoietic stem and progenitor cells (HSPCs). These findings indicate that Twist-1 is not only involved in the maintenance of HSC dormancy and self-renewal capacity but also implicated in the myeloid lineage fate choice of HSPCs. Exploration of the underlying mechanisms reveals that Runx1/c-Mpl/Tie2 regulatory pathway could possibly account for the observed effects caused by Twist-1 overexpression. Our study provides the first evidence supporting a role for Twist-1 in hematopoiesis.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, People's Republic of China.
authors.forename: Cheng-Ya
authors.initials: CY
authors.lastname: Dong
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Liu
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Wang
authors.forename: Bin-Xia
authors.initials: BX
authors.lastname: Yang
authors.forename: Qian
authors.initials: Q
authors.lastname: Ren
authors.forename: Hao-Yue
authors.initials: HY
authors.lastname: Liang
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Ma
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division; D019070:Cell Lineage / Q000235:genetics*; D000066673:Cell Self Renewal; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse
keywords: Hematopoietic stem cells; Myeloid progenitor cells; Self-renewal; Twist-1