Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential

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Abstract

Background

Several studies demonstrate the role of adipose mesenchymal stem cells (ASCs) in angiogenesis. The angiogenic mechanism has been ascribed to paracrine factors since these cells secrete a plenty of signal molecules and growth factors. Recently it has been suggested that besides soluble factors, extracellular vesicles (EVs) that include exosomes and microvesicles may play a major role in cell-to-cell communication. It has been shown that EVs are implicated in the angiogenic process.

Results

Herein we studied whether EVs released by ASCs may mediate the angiogenic activity of these cells. Our results demonstrated that ASC-derived EVs induced in vitro vessel-like structure formation by human microvascular endothelial cells (HMEC). EV-stimulated HMEC when injected subcutaneously within Matrigel in SCID mice formed vessels . Treatment of ASCs with platelet-derived growth factor (PDGF) stimulated the secretion of EVs, changed their protein composition and enhanced the angiogenic potential. At variance of EVs released in basal conditions, PDGF-EVs carried c-kit and SCF that played a role in angiogenesis as specific blocking antibodies inhibited in vitro vessel-like structure formation. The enhanced content of matrix metalloproteinases in PDGF-EVs may also account for their angiogenic activity.

Conclusions

Our findings indicate that EVs released by ASCs may contribute to the ASC-induced angiogenesis and suggest that PDGF may trigger the release of EVs with an enhanced angiogenic potential.

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Most cited references 45

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Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities.

S Gebre, P Levéen, Tobias Larsson … (1994)

Platelet-derived growth factor (PDGF) affects the growth, migration, and function in vitro of mesenchymal cells, but little is known about its normal physiological functions in vivo. We show here that mice deficient for PDGF B die perinatally and display several anatomical and histological abnormalities. Kidney glomerular tufts do not form, apparently because of absence of mesangial cells. Instead, a single or a few distended capillary loops fill the glomerular space. The heart and some large arteries dilate in late-stage embryos. Most PDGF B mutant embryos develop fatal hemorrhages just prior to birth. Their hematological status includes erythroblastosis, macrocytic anemia, and thrombocytopenia. On the basis of these findings, we conclude that PDGF B has crucial roles in vivo in establishing certain renal and circulatory functions.

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Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice.

Evelyne P Soriano (1994)

Platelet-derived growth factor, a major mitogen and chemoattractant for a number of cell types, is implicated in the processes of wound healing, tumorigenesis, and differentiation and is recognized by two receptors, alpha and beta. To begin understanding the role of these receptors in development, beta-receptor-deficient mice were generated by gene targeting in ES cells. Mutant mice are hemorrhagic, thrombocytopenic, and severely anemic, exhibit a defect in kidney glomeruli because of a lack of mesangial cells, and die at or shortly before birth. However, many cell types and tissues that express the receptor, including major blood vessels and the heart, appear normal in the absence of the receptor. These results indicate that whereas the beta receptor is essential in certain cell types during embryonic development, its broader role may be masked because of compensation by the alpha-subunit.

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Matrix metalloproteinases and angiogenesis.

Joyce Rundhaug (2015)

Matrix metalloproteinases (MMPs) are a family of enzymes that proteolytically degrade various components of the extracellular matrix (ECM). Angiogenesis is the process of forming new blood vessels from existing ones and requires degradation of the vascular basement membrane and remodeling of the ECM in order to allow endothelial cells to migrate and invade into the surrounding tissue. MMPs participate in this remodeling of basement membranes and ECM. However, it has become clear that MMPs contribute more to angiogenesis than just degrading ECM components. Specific MMPs have been shown to enhance angiogenesis by helping to detach pericytes from vessels undergoing angiogenesis, by releasing ECM-bound angiogenic growth factors, by exposing cryptic proangiogenic integrin binding sites in the ECM, by generating promigratory ECM component fragments, and by cleaving endothelial cell-cell adhesions. MMPs can also contribute negatively to angiogenesis through the generation of endogenous angiogenesis inhibitors by proteolytic cleavage of certain collagen chains and plasminogen and by modulating cell receptor signaling by cleaving off their ligand-binding domains. A number of inhibitors of MMPs that show antiangiogenic activity are already in early stages of clinical trials, primarily to treat cancer and cancer-associated angiogenesis. However, because of the multiple effects of MMPs on angiogenesis, careful testing of these MMP inhibitors is necessary to show that these compounds do not actually enhance angiogenesis.

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Author and article information

Contributors

Tatiana Lopatina

Stefania Bruno

Ciro Tetta

Natalia Kalinina

Massimo Porta

Giovanni Camussi

Journal

Journal ID (nlm-ta): Cell Commun Signal

Journal ID (iso-abbrev): Cell Commun. Signal

Title: Cell Communication and Signaling : CCS

Publisher: BioMed Central

ISSN (Electronic): 1478-811X

Publication date Collection: 2014

Publication date (Electronic): 11 April 2014

Volume: 12

Page: 26

Affiliations

[1 ]Department of Medical Sciences and Molecular Biotechnology Center, University of Torino, Corso Dogliotti 14, 10126, Torino, Italy

[2 ]EMEA LA Medical Board, Fresenius Medical CareAG & Co. KGaA, Bad Homburg 61346, Germany

[3 ]Department of Fundamental Medicine, Lomonosov Moscow State University, Lomonosovsky av. 31-5, 119192 Moscow, Russia

Article

Publisher ID: 1478-811X-12-26

DOI: 10.1186/1478-811X-12-26

PMC ID: 4022079

PubMed ID: 24725987

SO-VID: 35d92aac-a1d1-4241-94c2-88b627dec545

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential

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Abstract

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Most cited references 45

Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities.

Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice.

Matrix metalloproteinases and angiogenesis.

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