Twist-1, a novel regulator of hematopoietic stem cell self-renewal and myeloid lineage development.
Stem Cells
; 32(12): 3173-82, 2014 Dec.
Article
em En
| MEDLINE
| ID: mdl-25100001
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.
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MEDLINE
Assunto principal:
Células-Tronco Hematopoéticas
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Proteínas Nucleares
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Diferenciação Celular
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Linhagem da Célula
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Células Mieloides
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Proteína 1 Relacionada a Twist
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Autorrenovação Celular
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Hematopoese
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article