Pro-inflammatory cytokines activate hypoxia-inducible factor 3Œ± via epigenetic changes in mesenchymal stromal/stem cells
Authors: Matilde Valeria Ursini
Antonietta Coppola
Umberto Galderisi
Gilda Cobellis
Lucia Altucci
Lucia Scisciola
Francesca Cuomo
Ciro Maione
Amalia Forte
Giuseppina Liguori
Ilaria Caiafa
Chiara Botti
Marilena Cipollaro
Journal: Scientific Reports (2018)
Discipline: Multidisciplinary
Keywords: hMSCs; ischemic disorders; regeneration; angiogenesis; inflammation
Affiliations: Department of Biochemistry, Biophysics and General Pathology, Universit√† degli Studi della Campania L. Vanvitelli, Via L. De Crecchio, 7, 80138, Naples, Italy., Laboratorio di Patologia Clinica, Ospedale Santobono, Via M. Fiore 6, 80129, Naples, Italy., Department of Experimental Medicine, Universit√† degli Studi della Campania L. Vanvitelli, Via L. De Crecchio, 7, 80138, Naples, Italy., Istituto Nazionale Tumori, Struttura Complessa Oncologia Medica Melanoma Immunoterapia Oncologica e Terapia Innovativa, Via M. Semmola, 80131, Naples, Italy., Institute of Genetics and Biophysics, 'A. Buzzati-Traverso' (IGB), via P. Castellino, 111, 80131, Naples, Italy., Department of Biochemistry, Biophysics and General Pathology, Universit√† degli Studi della Campania L. Vanvitelli, Via L. De Crecchio, 7, 80138, Naples, Italy. .

Abstract:  Human mesenchymal stromal/stem cells (hMSCs) emerged as a promising therapeutic tool for ischemic disorders, due to their ability to regenerate damaged tissues, promote angiogenesis and reduce inflammation, leading to encouraging, but still limited results. The outcomes in clinical trials exploring hMSC therapy are influenced by low cell retention and survival in affected tissues, partially influenced by lesion's microenvironment, where low oxygen conditions (i.e. hypoxia) and inflammation coexist. Hypoxia and inflammation are pathophysiological stresses, sharing common activators, such as hypoxia-inducible factors (HIFs) and NF-Œ∫B. HIF1Œ± and HIF2Œ± respond essentially to hypoxia, activating pathways involved in tissue repair. Little is known about the regulation of HIF3Œ±. Here we investigated the role of HIF3Œ± in vitro and in vivo. Human MSCs expressed HIF3Œ±, differentially regulated by pro-inflammatory cytokines in an oxygen-independent manner, a novel and still uncharacterized mechanism, where NF-Œ∫B is critical for its expression. We investigated if epigenetic modifications are involved in HIF3Œ± expression by methylation-specific PCR and histone modifications. Robust hypermethylation of histone H3 was observed across HIF3A locus driven by pro-inflammatory cytokines. Experiments in a murine model of arteriotomy highlighted the activation of Hif3Œ± expression in infiltrated inflammatory cells, suggesting a new role for Hif3Œ± in inflammation in vivo. 

Retracted: No

PubPeer comments:
 Figure 1B appears to include a repeated image. ***  , 
 Figure 3B appears to contain multiple repeated bands, after adjusting sizes in some cases. Image shown inverted with contrast enhanced. ***  , 
 #2 aplicon 3 also has some apparent duplications  , 
 u201cPublished: 17 April 2020 Correction to: Scientific Reports https: doi.org 10.1038 s41598-018-24221-5, published online 11 April 2018 The original version of this Article contained errors (sic). In Figure 1b, panels for hypoxia, image for u201cscr siRNAu201d was a duplicate of image for u201c---u201d. Additionally, in Figure 3b, as a result of figure misassembly all images for controls for amplicon #1 and amplicon #2 were duplicates. This panel has been corrected. The original data for these images was provided in the Supplementary File, which has been updated to show which sections of the original data were used to assemble main figures. These errors have been corrected in the PDF and HTML versions of the Article, and in the accompanying Supplementary Information file.u201d , 
 Two images in Supplemental Figure 4b appear to show overlapping fields of view, but are described differently. ***  ,