title: Transcriptome sequencing wide functional analysis of human mesenchymal stem cells in response to TLR4 ligand.
abstract: Due to their multipotentiality and immunomodulation, human mesenchymal stem cells (hMSCs) are widely studied for the treatment of degenerative and inflammatory diseases. Transplantation of hMSCs to damaged tissue is a promising approach for tissue regeneration. However, the physiological mechanisms and regulatory processes of MSC trafficking to injured tissue are largely unexplored. Here, we evaluated the gene expression profile and migratory potential of hMSCs upon stimulation with the TLR4 ligand lipopolysaccharide (LPS). Using RNA sequencing, we identified unique induction patterns of interferon stimulated genes, cytokines and chemokines involved in chemotaxis and homing. The -950 to +50 bp regions of many of these LPS-responsive genes were enriched with putative binding motifs for the transcription factors (TFs) interferon regulatory factor (IRF1) and nuclear factor kappa B (NF-κB1, REL), which were also induced by LPS along with other TFs. Chromatin immunoprecipitation assays showed that IRF1 bound within their target genes promoter region. In addition, IRF1 attenuation significantly down-regulated interferon stimulated genes as well as key cytokines. Furthermore, using pharmacological inhibitors, we showed that the NF-κB and phosphatidylinositol 3-kinase (PI3K) pathways regulate the migratory and cytokines/chemokines response to LPS. These unprecedented data suggest that IRF1 and NF-κB orchestrate the TLR4-primed immunomodulatory response of hMSCs and that this response also involves the PI3K pathway.
authors.affiliation: Department of Molecular &Life Science, Hanyang University, Ansan, 15588, Republic of Korea.
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Institute of Natural Science &Technology, Hanyang University, Ansan, 15588, Republic of Korea.
authors.forename: Amitabh
authors.initials: A
authors.lastname: Das
authors.affiliation: Department of Molecular &Life Science, Hanyang University, Ansan, 15588, Republic of Korea.
authors.forename: Jin Choul
authors.initials: JC
authors.lastname: Chai
authors.affiliation: Department of Molecular &Life Science, Hanyang University, Ansan, 15588, Republic of Korea.
authors.forename: Bert
authors.initials: B
authors.lastname: Binas
authors.affiliation: Department of Molecular &Life Science, Hanyang University, Ansan, 15588, Republic of Korea.
authors.forename: Mi Ran
authors.initials: MR
authors.lastname: Choi
authors.affiliation: Department of Molecular &Life Science, Hanyang University, Ansan, 15588, Republic of Korea.
authors.forename: Kyoung Sun
authors.initials: KS
authors.lastname: Park
authors.affiliation: Department of Molecular &Life Science, Hanyang University, Ansan, 15588, Republic of Korea.
authors.forename: Young Seek
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Institute of Natural Science &Technology, Hanyang University, Ansan, 15588, Republic of Korea.
authors.forename: Kyoung Hwa
authors.initials: KH
authors.lastname: Jung
authors.affiliation: Department of Molecular &Life Science, Hanyang University, Ansan, 15588, Republic of Korea.|Department of Bionanotechnology, Hanyang University, Seoul, 04673, Republic of Korea.
authors.forename: Young Gyu
authors.initials: YG
authors.lastname: Chai
mesh_terms: D018507:Gene Expression Regulation, Developmental; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics*; D008024:Ligands; D008070:Lipopolysaccharides / Q000737:chemistry; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics; D059467:Transcriptome / Q000235:genetics
chemical_list: C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D008024:Ligands; D008070:Lipopolysaccharides; C498143:RELA protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D019869:Phosphatidylinositol 3-Kinases