An inter-disciplinary team of researchers, funded by the University of Torontos Medicine by Design,hasgeneratedfunctional blood vessel cells found in the liver from stem cells a discovery thatoffersan opportunityto study the rolethe cellsplayin liver developmentand diseaseprogression, and which couldlead tonew therapies to treat hemophilia A.

Thestudy, titledGeneration of Functional Liver Sinusoidal Endothelial Cells from Human Pluripotent Stem Cell-Derived Venous Angioblasts,waspublished this week in Cell Stem Cell. Itrepresents a collaborative effort betweenbasic and clinical researchersat U of T and the University Health Network (UHN)with expertise in stem celland computationalbiology,human liver physiology and functionand liver transplantation.

It alsodraws onprevious Medicine by Design-funded research that led to the creationin 2018of the first single-cell map of the human liver.

By combining insights from developmental biology and liver anatomy with thecellatlasof the human liver,we were able to generateand validatefunctional human liver vasculature from stem cells, saysBlair Gage,apost-doctoral researcher at the McEwen Stem Cell Institute at UHNand lead author ofthestudy.Nowwe canmove forwardto use these liver endothelial cells tobetterunderstandtheir role in liver functionand to develop new therapies to treat disorderssuch ashemophilia A.

Theinterdisciplinary researchteam also includes:JeffLiu,research associate atU of TsDonnelly Centrefor Cellular andBiomolecularResearch;Brendan Innes, a PhD candidate at the Donnelly Centre and in thedepartment ofmolecular genetics in the Faculty of Medicine;Sonya MacParland, scientist in themulti-organ transplant program at theToronto General Hospital Research Institute andan assistant professor in U of Ts departments of immunology andlaboratory medicine and pathobiology; Ian McGilvray,senior scientist at themulti-organ transplant program at theToronto General Hospital Research Institute and a professorinU of Ts department of surgery;Gary Bader, professor at the Donnelly Centreandthedepartment ofmolecular genetics; andGordon Keller,director andsenior scientist at theMcEwen Stem Cell Institute at UHNandprofessor in U of Ts department of medical biophysics.

Researchersinthe Keller lab had the goal of generatinga functional liver vasculature cell type known as liver sinusoidal cells (LSECs)fromhuman pluripotent stem cells (hPSCs) cells that can self-renew and have the potential to turn into any other cell type in the human body. LSECs are essential for normal liver function and represent the main source of factor VIII,a blood-clotting protein that is missing or defective in patients with hemophilia A.

However, the teamhad todemonstratethatthecellstheyhadmadein the labhad thesamespecializedgenetic and functionalfeaturesasthose in thehuman liver.So they turned to the work of MacParland, Bader and McGilvray,whoin the first phase ofMedicine by Designs team projectfundingdescribed amolecularmap of the cell types in the adult liver.Thatresearchhascontributed totheHuman Cell Atlasan international effort to create comprehensive reference maps of all human cellsand last yearattracted follow-on funding from the Chan Zuckerberg Initiative.

This paper uses our human liver map as a guide to know if the cells beinggeneratedaretherightones through collaboration with Gary Baders group, says MacParland.The work really highlights thestrengthof MedicinebyDesignin bringingtogether researchers from multiple institutionstofocus on a common goal.

With Bader and Lius help, Keller lab researchers were able to use the MacParlandhuman livermapto show that thehPSC-derivedendothelialcellsthey had generatedshared manyof thefeatures found innormal liver vasculature. The Keller lab team then brought Innes on board toformat thedatafromthehPSC-derived LSECsfor the research communitytoeasilyexplorethe molecular profile of these cells.

This research was supported by Medicine by Design, which receives funding from the federal governmentsCanada First Research Excellence Fundand by theCanadian Institutes of Health Research.

The work continues in a current Medicine by Design-funded team projectled by Kellerthat aims to make other key liver cell types and put together the pieces to get functional tissueswith the goal of developing new cell-based therapies for liver-related diseases.That project is part ofanew $20-million round of team project fundingthat Medicine by Design announced late last year.

Medicine by Designbrings togetherinvestigatorsfromdifferent disciplinesatU of T and its affiliated hospitals to advance new discoveries in regenerative medicine and accelerate them toward clinical impact.Medicine by Designwill host ameeting of the Human Cell Atlass Development and Pediatric Atlasin July 2021in Toronto.

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Researchers at U of T use stem cells to grow functional blood vessel cells found in liver - News@UofT