title: DDIT4 regulates mesenchymal stem cell fate by mediating between HIF1α and mTOR signalling.
abstract: Stem cell fate decisions to remain quiescent, self-renew or differentiate are largely governed by the interplay between extracellular signals from the niche and the cell intrinsic signal cascades and transcriptional programs. Here we demonstrate that DNA Damage Inducible Transcript 4 (DDIT4) acts as a link between HIF1α and mTOR signalling and regulation of adult stem cell fate. Global gene expression analysis of mesenchymal stem cells (MSC) derived from single clones and live RNA cell sorting showed a direct correlation between DDIT4 and differentiation potentials of MSC. Loss and gain of function analysis demonstrated that DDIT4 activity is directly linked to regulation of mTOR signalling, expression of pluripotency genes and differentiation. Further we demonstrated that DDIT4 exert these effects down-stream to HIF1α. Our findings provide an insight in regulation of adult stem cells homeostasis by two major pathways with opposing functions to coordinate between states of self-renewal and differentiation.
authors.affiliation: Division of Tissue Engineering and Biophotonics, Dental Institute, King's College London, Tower Wing, Guy's Hospital, London, SE1 9RT. UK.
authors.forename: Borzo
authors.initials: B
authors.lastname: Gharibi
authors.affiliation: Division of Tissue Engineering and Biophotonics, Dental Institute, King's College London, Tower Wing, Guy's Hospital, London, SE1 9RT. UK.
authors.forename: Mandeep
authors.initials: M
authors.lastname: Ghuman
authors.affiliation: Division of Tissue Engineering and Biophotonics, Dental Institute, King's College London, Tower Wing, Guy's Hospital, London, SE1 9RT. UK.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Hughes
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D015870:Gene Expression / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: C469991:DDIT4 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases