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The development of engraftable, long-term reconstituting hematopoietic stem cells (LT-HSC) from human pluripotent stem cells (hPSC) has been a long-sought goal. Since HSCs are formed by a subset of endothelial cells in the ventral part of the dorsal aorta, we analyzed heartbeat-mediated pulsatile displacement experienced by the walls of the dorsal aorta in zebrafish embryos. We found that pulsation-mediated circumferential stretch was restricted to the ventral part of the dorsal aorta and activated Piezo1 to stimulate LT-HSC formation. Stimulation of pulsation or Yoda1-mediated Piezo1 activation promoted the formation of de novo LT-HSCs from hemogenic endothelial cells derived from murine embryos or human pluripotent stem cells. These HSCs gave long-term multilineage reconstitution of hematopoietic cells upon transplantation into immunocompromised mice. The formation of transgene-free human LT-HSCs that can engraft and reconstitute the hematopoietic system will facilitate the generation of off-the-shelf HSCs from hPSCs for use in cellular therapies.