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

Dev Cell. 2020 Feb 24;52(4):446-460.e5. doi: 10.1016/j.devcel.2020.01.006. Epub 2020 Feb 6.


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.

Keywords: RUNX1; Rho-GTPase; YAP; blood flow; cyclic stretch; endothelial-to-hematopoietic transition; hematopoietic stem cells; hemogenic endothelium; organ-on-a-chip; zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / cytology
  • Aorta / embryology
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Differentiation
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism*
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / metabolism
  • Endothelium, Vascular / cytology*
  • Endothelium, Vascular / metabolism
  • Hematopoiesis*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / physiology
  • Hemodynamics
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / physiology
  • Mechanotransduction, Cellular*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Zebrafish
  • rho GTP-Binding Proteins / metabolism


  • Cell Cycle Proteins
  • Core Binding Factor Alpha 2 Subunit
  • RUNX1 protein, human
  • Transcription Factors
  • YY1AP1 protein, human
  • rho GTP-Binding Proteins