YAP Regulates Hematopoietic Stem Cell Formation in Response to the Biomechanical Forces of Blood Flow.
Dev Cell
; 52(4): 446-460.e5, 2020 02 24.
Article
en En
| MEDLINE
| ID: mdl-32032546
Hematopoietic stem and progenitor cells (HSPCs), first specified from hemogenic endothelium (HE) in the ventral dorsal aorta (VDA), support lifelong hematopoiesis. Their de novo production promises significant therapeutic value; however, current in vitro approaches cannot efficiently generate multipotent long-lived HSPCs. Presuming this reflects a lack of extrinsic cues normally impacting the VDA, we devised a human dorsal aorta-on-a-chip platform that identified Yes-activated protein (YAP) as a cyclic stretch-induced regulator of HSPC formation. In the zebrafish VDA, inducible Yap overexpression significantly increased runx1 expression in vivo and the number of CD41+ HSPCs downstream of HE specification. Endogenous Yap activation by lats1/2 knockdown or Rho-GTPase stimulation mimicked Yap overexpression and induced HSPCs in embryos lacking blood flow. Notably, in static human induced pluripotent stem cell (iPSC)-derived HE culture, compound-mediated YAP activation enhanced RUNX1 levels and hematopoietic colony-forming potential. Together, our findings reveal a potent impact of hemodynamic Rho-YAP mechanotransduction on HE fate, relevant to de novo human HSPC production.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
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Células Madre Hematopoyéticas
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Endotelio Vascular
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Proteínas de Ciclo Celular
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Mecanotransducción Celular
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Subunidad alfa 2 del Factor de Unión al Sitio Principal
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Células Madre Pluripotentes Inducidas
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Hematopoyesis
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Dev Cell
Asunto de la revista:
EMBRIOLOGIA
Año:
2020
Tipo del documento:
Article