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YAP Regulates Hematopoietic Stem Cell Formation in Response to the Biomechanical Forces of Blood Flow

Authors: 
Lundin V, Sugden WW, Theodore LN, Sousa PM, Han A, Chou S, Wrighton PJ, Cox AG, Ingber DE, Goessling W, Daley GQ, North TE
Citation: 
Dev Cell. 2020;[Epub ahead of print] doi:10.1016/j.devcel.2020.01.006
Abstract: 
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.
Epub: 
Yes
Organism or Cell Type: 
zebrafish
Delivery Method: 
microinjection