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  3. Hypoxia-induced HIF1α activation regulates small extracellular vesicle release in human embryonic kidney cells

Hypoxia-induced HIF1α activation regulates small extracellular vesicle release in human embryonic kidney cells

  • Sci Rep. 2022 Jan 27;12(1):1443. doi: 10.1038/s41598-022-05161-7.
Ana Muñiz-García 1 2,  Montserrat Romero 2 3 4,  Juan Manuel Falcόn-Perez 5 6 7,  Patricia Murray 1,  Antonio Zorzano 2 3 4,  Silvia Mora 8 9 10
Affiliations

Affiliations

  • 1 Department of Molecular Physiology and Cell Signalling (Formerly Dpt. Cellular and Molecular Physiology), The University of Liverpool, Liverpool, L69 3BX, UK.
  • 2 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 13, 08028, Barcelona, Spain.
  • 3 Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
  • 4 CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
  • 5 Exosomes Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain.
  • 6 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029, Madrid, Spain.
  • 7 IKERBASQUE, Basque Foundation for Science, 48015, Bilbao, Bizkaia, Spain.
  • 8 Department of Molecular Physiology and Cell Signalling (Formerly Dpt. Cellular and Molecular Physiology), The University of Liverpool, Liverpool, L69 3BX, UK. smora@ub.edu.
  • 9 Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain. smora@ub.edu.
  • 10 Institute of Biomedicine, University of Barcelona, 08028, Barcelona, Spain. smora@ub.edu.
PMID: 35087095 DOI: 10.1038/s41598-022-05161-7
Abstract

Extracellular vesicles (EVs) are membrane enclosures released by eukaryotic cells that carry bioactive molecules and serve to modulate biological responses in recipient cells. Both increased EV release and altered EV composition are associated with the development and progression of many pathologies including Cancer. Hypoxia, a feature of rapidly growing solid tumours, increases the release of EVs. However, the molecular mechanisms remain unknown. The hypoxia inducible factors (HIFs) are transcription factors that act as major regulators of the cellular adaptations to hypoxia. Here, we investigated the requirement of HIF pathway activation for EV release in Human Embryonic Kidney Cells (HEK293). Time course experiments showed that EV release increased concomitantly with sustained HIF1α and HIF2α activation following the onset of hypoxia. shRNA mediated knock-down of HIF1α but not HIF2α abrogated the effect of hypoxia on EV release, suggesting HIF1α is involved in this process. However, stabilization of HIF proteins in normoxic conditions through: (i) heterologous expression of oxygen insensitive HIF1α or HIF2α mutants in normoxic cells or (ii) chemical inhibition of the prolyl hydroxylase 2 (PHD2) repressor protein, did not increase EV release, suggesting HIF activation alone is not sufficient for this process. Our findings suggest HIF1α plays an important role in the regulation of EV release during hypoxia in HEK293 cells, however Other hypoxia triggered mechanisms likely contribute as stabilization of HIF1α alone in normoxia is not sufficient for EV release.

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