Flow-Induced Yap/Taz Signaling Balances Endothelial and Hematopoietic Stem Cell Fates

Area of Science:

• Developmental Biology
• Cell Biology
• Biophysics

Background:

• Mechanical forces from blood flow are critical for hematopoietic stem and progenitor cell (HSPC) generation during embryogenesis.
• The molecular mechanisms linking hemodynamic cues to endothelial-to-hematopoietic (EHT) transition are not fully understood.
• YAP mechanotransduction was previously identified as a key regulator integrating physical forces with EHT.

Purpose of the Study:

• To elucidate the molecular mechanisms by which hemodynamic forces regulate EHT.
• To investigate the role of the Piezo1/YAP axis in sensing mechanical forces for EHT.
• To differentiate the roles of YAP and its paralogue TAZ in HSPC production.

Main Methods:

• Utilized human induced pluripotent stem cell-derived hemogenic endothelium (HE) and zebrafish embryos.
• Investigated YAP signaling activation via the Piezo1 ion channel in response to hemodynamic forces.
• Performed comprehensive scRNA-sequencing on YAP/TAZ gain-of-function and yap-deficient zebrafish cells.
• Analyzed Tead co-factor requirement and TAZ's interaction with Runx1.

Main Results:

• Hemodynamic forces activate YAP signaling through Piezo1 in human iPSC-derived HE and zebrafish embryos.
• YAP and TAZ exhibit both shared and distinct roles in EHT, with Tead being essential for YAP/TAZ-mediated HSPC control.
• YAP/TAZ promotes HSC production by upregulating self-renewal and cell cycle programs, while TAZ uniquely enhances Runx1 activity.
• YAP and TAZ have distinct effects on metabolic and endothelial gene programs, with TAZ overactivation favoring an endothelial fate.

Conclusions:

• The Piezo1/YAP axis is a crucial mediator of hemodynamic force sensing for EHT.
• YAP and TAZ play complex, partially separable roles in regulating HSPC production and fate.
• Findings offer insights into optimizing in vitro hematopoietic differentiation systems by incorporating biomechanical cues.