Mesenchymal Stem Cells Exhibit Regulated Exocytosis in Response to Chemerin and IGF

Kumar, Jothi, Holmberg, Christopher, Balabanova, Silvia ORCID: 0000-0001-6989-8099, Borysova, Lyudmyla, Burdyga, Theodor, Beynon, Rob ORCID: 0000-0003-0857-495X, Dockray, Graham and Varro, Andrea (2015) Mesenchymal Stem Cells Exhibit Regulated Exocytosis in Response to Chemerin and IGF. PLOS ONE, 10 (10). e0141331-.

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Abstract

Mesenchymal stem cells (MSCs) play important roles in tissue repair and cancer progression. Our recent work suggests that some mesenchymal cells, notably myofibroblasts exhibit regulated exocytosis resembling that seen in neuroendocrine cells. We now report that MSCs also exhibit regulated exocytosis. Both a G-protein coupled receptor agonist, chemerin, and a receptor tyrosine kinase stimulant, IGF-II, evoked rapid increases in secretion of a marker protein, TGFβig-h3. The calcium ionophore, ionomycin, also rapidly increased secretion of TGFβig-h3 while inhibitors of translation (cycloheximide) or secretory protein transport (brefeldin A) had no effect, indicating secretion from preformed secretory vesicles. Inhibitors of the chemerin and IGF receptors specifically reduced the secretory response. Confocal microscopy of MSCs loaded with Fluo-4 revealed chemerin and IGF-II triggered intracellular Ca2+ oscillations requiring extracellular calcium. Immunocytochemistry showed co-localisation of TGFβig-h3 and MMP-2 to secretory vesicles, and transmission electron-microscopy showed dense-core secretory vesicles in proximity to the Golgi apparatus. Proteomic studies on the MSC secretome identified 64 proteins including TGFβig-h3 and MMP-2 that exhibited increased secretion in response to IGF-II treatment for 30min and western blot of selected proteins confirmed these data. Gene ontology analysis of proteins exhibiting regulated secretion indicated functions primarily associated with cell adhesion and in bioassays chemerin increased adhesion of MSCs and adhesion, proliferation and migration of myofibroblasts. Thus, MSCs exhibit regulated exocytosis that is compatible with an early role in tissue remodelling.

Item Type:	Article
Uncontrolled Keywords:	Cells, Cultured, Secretory Vesicles, Mesenchymal Stem Cells, Humans, Calcium, Intercellular Signaling Peptides and Proteins, Transforming Growth Factor beta, Somatomedins, Proteome, Chemokines, Culture Media, Conditioned, Reproducibility of Results, Proteomics, Cell Adhesion, Cell Proliferation, Cell Movement, Exocytosis, Calcium Signaling, Protein Transport
Depositing User:	Symplectic Admin
Date Deposited:	20 Jan 2016 09:51
Last Modified:	15 Dec 2022 11:47
DOI:	10.1371/journal.pone.0141331
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/2047521

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