title: Lineage-Specific Differentiation Is Influenced by State of Human Pluripotency.
abstract: Human pluripotent stem cells (hPSCs) have been reported in naive and primed states. However, the ability to generate mature cell types remains the imperative property for utility of hPSCs. Here, we reveal that the naive state enhances self-renewal while restricting lineage differentiation in vitro to neural default fate. Molecular analyses indicate expression of multiple lineage-associated transcripts in naive hPSCs that failed to predict biased functional differentiation capacity. Naive hPSCs can be converted to primed state over long-term serial passage that permits recovery of multi-germ layer differentiation. Suppression of OCT4 but not NANOG allows immediate recovery directly from naive state. To this end, we identified chemical inhibitors of OCT4 that restore naive hPSC differentiation. Our study reveals unique cell-fate restrictions in human pluripotent states and provides an approach to overcome these barriers that harness both efficient naive hPSC growth while maintaining in vitro differentiation essential for hPSC applications.
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4K1, Canada.
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4K1, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Laronde
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4K1, Canada.
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Collins
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4K1, Canada.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Shapovalova
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4K1, Canada.
authors.forename: Borko
authors.initials: B
authors.lastname: Tanasijevic
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4K1, Canada.
authors.forename: Jamie D
authors.initials: JD
authors.lastname: McNicol
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4K1, Canada.
authors.forename: Aline
authors.initials: A
authors.lastname: Fiebig-Comyn
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4K1, Canada.
authors.forename: Yannick D
authors.initials: YD
authors.lastname: Benoit
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4K1, Canada.
authors.forename: Jung Bok
authors.initials: JB
authors.lastname: Lee
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4K1, Canada.
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Mitchell
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1280 Main Street West, MDCL 5029, Hamilton, ON L8S 4K1, Canada; Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada. Electronic address: mbhatia@mcmaster.ca.
authors.forename: Mickie
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D065150:Cellular Reprogramming / Q000235:genetics*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005855:Germ Layers / Q000166:cytology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D000071317:Nanog Homeobox Protein / Q000378:metabolism; D009761:Nystatin / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology*; D012313:RNA / Q000235:genetics; D013724:Teratoma / Q000378:metabolism
chemical_list: D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D009761:Nystatin; D012313:RNA
keywords: differentiation; human pluripotency; lineage specification; naïve state; reprogramming