Therapeutic correction of hemophilia A by transplantation of hPSC-derived liver sinusoidal endothelial cell progenitors

Blair K Gage; Simone Merlin; Cristina Olgasi; Antonia Follenzi; Gordon M Keller

doi:10.1016/j.celrep.2022.110621

Therapeutic correction of hemophilia A by transplantation of hPSC-derived liver sinusoidal endothelial cell progenitors

Cell Rep. 2022 Apr 5;39(1):110621. doi: 10.1016/j.celrep.2022.110621.

Authors

Blair K Gage¹, Simone Merlin², Cristina Olgasi², Antonia Follenzi², Gordon M Keller³

Affiliations

¹ McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G1L7, Canada. Electronic address: [email protected].
² Department of Health Sciences, School of Medicine, University of Piemonte Orientale, 28100 Novara, Italy.
³ McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G1L7, Canada. Electronic address: [email protected].

PMID: 35385743
DOI: 10.1016/j.celrep.2022.110621

Abstract

Liver sinusoidal endothelial cells (LSECs) form the predominant microvasculature in the liver where they carry out many functions including the secretion of coagulation factor VIII (FVIII). To investigate the early origins of this lineage, we develop an efficient and scalable protocol to produce human pluripotent stem cell (hPSC)-derived LSEC progenitors characterized as venous endothelial cells (VECs) from different mesoderm subpopulations. Using a sensitive and quantitative vascular competitive transplantation assay, we demonstrate that VECs generated from BMP4 and activin A-induced KDR⁺CD235a/b⁺ mesoderm are 50-fold more efficient at LSEC engraftment than venous cells from BMP4 and WNT-induced KDR⁺CD235a/b^- mesoderm. When transplanted into immunocompromised hemophilia A mice (NSG-HA), these VECs engraft the liver, proliferate, and mature to functional LSECs that secrete bioactive FVIII capable of correcting the bleeding phenotype. Together, these findings highlight the importance of appropriate mesoderm induction for generating hPSC-derived LSECs capable of functioning in a preclinical model of hemophilia A.

Keywords: CP: Cell biology; CP: Stem cell research; FVIII; cell therapy; competitive transplantation; hPSCs; hemophilia A; liver sinusoidal endothelial cells; mesoderm; venous endothelial cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Endothelial Progenitor Cells*
Hemophilia A* / genetics
Hemophilia A* / therapy
Hepatocytes
Liver
Mice
Pluripotent Stem Cells*

Grants and funding

FDN159937/CIHR/Canada