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

Vanessa Lundin; Wade W Sugden; Lindsay N Theodore; Patricia M Sousa; Areum Han; Stephanie Chou; Paul J Wrighton; Andrew G Cox; Donald E Ingber; Wolfram Goessling; George Q Daley; Trista E North

doi:10.1016/j.devcel.2020.01.006

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.

Authors

Affiliations

¹ Stem Cell Program, Division of Pediatric Hematology and Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
² Stem Cell Program, Division of Pediatric Hematology and Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
³ Stem Cell Program, Division of Pediatric Hematology and Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
⁴ Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁵ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA.
⁶ Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Stem Cell Program, Division of Pediatric Hematology and Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁸ Stem Cell Program, Division of Pediatric Hematology and Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: [email protected].

Abstract

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding