title: Pluripotent and Multipotent Stem Cells Display Distinct Hypoxic miRNA Expression Profiles.
abstract: MicroRNAs are reported to have a crucial role in the regulation of self-renewal and differentiation of stem cells. Hypoxia has been identified as a key biophysical element of the stem cell culture milieu however, the link between hypoxia and miRNA expression in stem cells remains poorly understood. We therefore explored miRNA expression in hypoxic human embryonic and mesenchymal stem cells (hESCs and hMSCs). A total of 50 and 76 miRNAs were differentially regulated by hypoxia (2% O2) in hESCs and hMSCs, respectively, with a negligible overlap of only three miRNAs. We found coordinate regulation of precursor and mature miRNAs under hypoxia suggesting their regulation mainly at transcriptional level. Hypoxia response elements were located upstream of 97% of upregulated hypoxia regulated miRNAs (HRMs) suggesting hypoxia-inducible-factor (HIF) driven transcription. HIF binding to the candidate cis-elements of specific miRNAs under hypoxia was confirmed by Chromatin immunoprecipitation coupled with qPCR. Role analysis of a subset of upregulated HRMs identified linkage to reported inhibition of differentiation while a downregulated subset of HRMs had a putative role in the promotion of differentiation. MiRNA-target prediction correlation with published hypoxic hESC and hMSC gene expression profiles revealed HRM target genes enriched in the cytokine:cytokine receptor, HIF signalling and pathways in cancer. Overall, our study reveals, novel and distinct hypoxia-driven miRNA signatures in hESCs and hMSCs with the potential for application in optimised culture and differentiation models for both therapeutic application and improved understanding of stem cell biology.
authors: Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Delhi, India-110016.
authors: Rahul
authors: R
authors: Agrawal
authors: Guy Hilton Research Centre, Institute of Science and Technology in Medicine, University of Keele, Thornburrow Drive, Hartshill, Stoke-on-Trent, Staffordshire, ST4 7QB, United Kingdom.
authors: Tina P
authors: TP
authors: Dale
authors: Guy Hilton Research Centre, Institute of Science and Technology in Medicine, University of Keele, Thornburrow Drive, Hartshill, Stoke-on-Trent, Staffordshire, ST4 7QB, United Kingdom.|College of Pharmacy, Al-Mustansiriyah University, Baghdad, Iraq.
authors: Mohammed A
authors: MA
authors: Al-Zubaidi
authors: Department of Pathology, All India Institute of Medical Sciences, New Delhi, India-110029.
authors: Prit
authors: P
authors: Benny Malgulwar
authors: Guy Hilton Research Centre, Institute of Science and Technology in Medicine, University of Keele, Thornburrow Drive, Hartshill, Stoke-on-Trent, Staffordshire, ST4 7QB, United Kingdom.
authors: Nicholas R
authors: NR
authors: Forsyth
authors: Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Delhi, India-110016.
authors: Ritu
authors: R
authors: Kulshreshtha
mesh_terms: D015687:Cell Hypoxia; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D035683:MicroRNAs