title: Gli3-mediated hedgehog inhibition in human pluripotent stem cells initiates and augments developmental programming of adult hematopoiesis.
abstract: Programs that control early lineage fate decisions and transitions from embryonic to adult human cell types during development are poorly understood. Using human pluripotent stem cells (hPSCs), in the present study, we reveal reduction of Hedgehog (Hh) signaling correlates to developmental progression of hematopoiesis throughout human ontogeny. Both chemical- and gene-targeting–mediated inactivation of Hh signaling augmented hematopoietic fate and initiated transitions from embryonic to adult hematopoiesis, as measured by globin regulation in hPSCs. Inhibition of the Hh pathway resulted in truncation of Gli3 to its repressor, Gli3R, and was shown to be necessary and sufficient for initiating this transition. Our results reveal an unprecedented role for Hh signaling in the regulation of adult hematopoietic specification, thereby demonstrating the ability to modulate the default embryonic programs of hPSCs.
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Hamilton, Ontario, Canada.
authors.forename: Brendan A S
authors.initials: BA
authors.lastname: McIntyre
authors.forename: Veronica
authors.initials: V
authors.lastname: Ramos-Mejia
authors.forename: Shravanti
authors.initials: S
authors.lastname: Rampalli
authors.forename: Rami
authors.initials: R
authors.lastname: Mechael
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Cantas
authors.initials: C
authors.lastname: Alev
authors.forename: Guojun
authors.initials: G
authors.lastname: Sheng
authors.forename: Mickie
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000378:metabolism / Q000502:physiology; D001773:Blood Cells / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D046228:Microarray Analysis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D059467:Transcriptome; D000074290:Zinc Finger Protein Gli3
chemical_list: C065683:GLI3 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3