<scp>PIEZO1</scp> Activation‐Mediated Generation of Transgene‐Free Long‐Term Hematopoietic Stem Cells
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.
Authors
- Taylor C. Patch
- Bradley W. Blaser (ORCID: https://orcid.org/0000-0002-3168-5423)
- Cintia Elisabeth Gomez Limia
- Lalit Sehgal
- Elliott J. Hagedorn (ORCID: https://orcid.org/0000-0002-3824-3249)
- Giorgia Scapin
- Emily M. Teets (ORCID: https://orcid.org/0000-0002-0249-277X)
- Jennifer L. Cillis
- Priyanka R. Dharampuriya
- Calum A. MacRae (ORCID: https://orcid.org/0000-0001-5181-2664)
- Dhvanit I. Shah (ORCID: https://orcid.org/0000-0002-3173-2402)
- Wenqiang Du (ORCID: https://orcid.org/0000-0003-2605-4325)
- Gabriel Musso (ORCID: https://orcid.org/0000-0001-8778-8248)
- Yichen Ding (ORCID: https://orcid.org/0000-0002-6242-3506)
- Marie Goulard
- Tzung K. Hsiai (ORCID: https://orcid.org/0000-0003-1734-0792)
- Heidi Anderson
- Caitlyn R. Curley
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Harvard University (US)
- University of California, Los Angeles (US)
- Boston Children's Museum (US)
- Harvard Stem Cell Institute (US)
- The Ohio State University (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- American Journal of Hematology
- Published
- 2025-05-04
- DOI
- https://doi.org/10.1002/ajh.27689
- Citations
- 4
- Primary Topic
- Zebrafish Biomedical Research Applications
- Type
- article
- Field-Weighted Citation Impact
- 4.61
Funders
- American Society of Hematology
- St. Baldrick's Foundation
- Pelotonia
- National Heart, Lung, and Blood Institute
- National Institute of Diabetes and Digestive and Kidney Diseases