1. YAP Regulates Hematopoietic Stem Cell Formation in Response to the Biomechanical Forces of Blood Flow
- Author
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Areum Han, Wolfram Goessling, Vanessa Lundin, Donald E. Ingber, Andrew G. Cox, Wade W. Sugden, Stephanie Chou, Patricia Sousa, Lindsay Theodore, George Q. Daley, Trista E. North, and Paul J. Wrighton
- Subjects
rho GTP-Binding Proteins ,Embryo, Nonmammalian ,Cellular differentiation ,Induced Pluripotent Stem Cells ,Cell Cycle Proteins ,Biology ,Mechanotransduction, Cellular ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Dorsal aorta ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Humans ,Progenitor cell ,Induced pluripotent stem cell ,Molecular Biology ,Aorta ,Zebrafish ,030304 developmental biology ,Hemogenic endothelium ,0303 health sciences ,Hemodynamics ,Hematopoietic stem cell ,Cell Differentiation ,Cell Biology ,Hematopoietic Stem Cells ,Hematopoiesis ,Cell biology ,Haematopoiesis ,medicine.anatomical_structure ,RUNX1 ,chemistry ,Core Binding Factor Alpha 2 Subunit ,Endothelium, Vascular ,030217 neurology & neurosurgery ,Transcription Factors ,Developmental Biology - 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.
- Published
- 2020
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