The Hippo pathway is a signaling pathway that regulates the self-renewal and differentiation of hematopoietic stem cells (HSCs). Mechanical stresses and the presence of VEGF activate the pathway, which promotes HSC retention in the bone marrow. MST1/2 and XMU-MP-1, respectively, suppress HSC expansion and ROS signaling. LATS1/2 and YAP/TAZ copolarize and form a complex in the cytosol with Scribble-Cdc42 GTPases, which controls HSC self-renewal and asymmetric cell division. Mechanical cyclic stretch influences embryonic aortic endothelial cell differentiation into HSCs by activating Rho GTPase, an upstream regulator of YAP-mediated mechanotransduction, which leads to RUNX1 expression for endothelial-hematopoietic transition (EHT).