Urokinase receptor mediates mobilization, migration, and differentiation of mesenchymal stem cells

Vallabhaneni, Krishna C.; Tkachuk, Sergey; Kiyan, Yulia; Shushakova, Nelli; Haller, Hermann; Dumler, Inna; Eden, Gabriele

doi:10.1093/cvr/cvq362

Cited by 47 publications

(51 citation statements)

References 48 publications

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“…uPAR function in cell differentiation seems to be of a general nature. As shown previously, uPAR governs VSMC phenotypic modulations from contractile to proinflammatory phenotype and regulates MSC differentiation to VSMC [8,23]. Therefore, a scenario could be suggested that in atherosclerotic vessels uPAR may initiate osteogenic differentiation not only in MSC but in VSMC and most likely in EC as well.…”

Section: Discussionmentioning

confidence: 62%

“…aSMA-positive areas of atherosclerotic plaques examined for C5aR expression in our immunohistological studies may therefore include several lineages, primarily VSMC and MSC. We have reported recently that uPAR deficiency results in a strong inhibition of MSC mobilization from the bone marrow and their engraftment at the site of vascular injury [8]. These abilities of uPAR may additionally contribute to the observed impaired ossification of aortic sinus wall in uPAR -/ -/LDLR -/ -versus uPAR + / + /LDLR -/ -mice.…”

Section: Discussionmentioning

confidence: 96%

“…We have shown previously that the multifunctional urokinase receptor uPAR is an important mediator of the anaphylatoxin C5a/C5a receptor (C5aR) complement cascade controlling C5aR expression, C5aR-directed signaling, and related functional effects in kidney mesangial cells and in alveolar macrophages in vitro and in vivo [6,7]. Our recent findings revealed one further novel function of uPAR as a regulator of differentiation and mobilization of bone marrow-derived mesenchymal stem cells (MSC) and of their engraftment at the place of injury [8]. MSC, which are adult stem cells retaining self-renewal capability and unique multilineage potential [9], have emerged as the most promising candidate for bone repair.…”

Section: Introductionmentioning

confidence: 83%

“…*P < 0.05. Color images available online at www.liebertpub.com/scd VSMC and in VSMC phenotypic modulations [8,23]. Our previous studies point to uPARs ability to interfere with the complement system and, in particular, to control C5aR expression and to affect by this way C5aR-directed functional effects [6,7].…”

Section: Fig 1 Mesenchymal Stem Cells (Msc) Undergo Differentiationmentioning

confidence: 92%

“…Lentiviral small interfering RNA (siRNA) vectors were designed and cloned, and lentiviral vectors were produced by transient transfection of human embryonic kidney-293T cells and used for MSC transfection as described previously [8]. For uPAR overexpression, lentiviral vector pWPTS-GFP (kindly provided by Didier Trono, Department of Genetics and Microbiology, Faculty of Medicine, University of Geneva, Switzerland) was modified by ligating synthetic oligonucleotide duplex in SalI and BamHI restriction sites.…”

Section: Lentiviral Transfection and Nucleofectionmentioning

confidence: 99%

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Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Anaraki

Patecki²,

Larmann³

et al. 2014

Stem Cells and Development

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Vascular calcification is a severe consequence of several pathological processes with a lack of effective therapy. Recent studies suggest that circulating and resident mesenchymal stem cells (MSC) contribute to the osteogenic program of vascular calcification. Molecular mechanisms underlying MSC osteogenic potential and differentiation remain, however, sparsely explored. We investigated a role for the complement receptor C5aR in these processes. We found that expression of C5aR was upregulated upon differentiation of human MSC to osteoblasts. C5aR inhibition by silencing and specific antagonist impaired osteogenic differentiation. We demonstrate that C5aR expression upon MSC differentiation was regulated by the multifunctional urokinase receptor (uPAR). uPAR targeting by siRNA resulted in complete abrogation of C5aR expression and consequently in the inhibition of MSC-osteoblast differentiation. We elucidated the NFkB pathway as the mechanism utilized by the uPAR-C5aR axis. MSC treatment with the NFkB inhibitor completely blocked the differentiation process. Nuclear translocation of the p65 RelA component of the NFkB complex was induced under osteogenic conditions and impaired by the inhibition of uPAR or C5aR. Dual-luciferase reporter assays demonstrated enhanced NFkB signaling upon MSC differentiation, whereas uPAR and C5aR downregulation lead to inhibition of the NFkB activity. We show involvement of the Erk1/2 kinase in this cascade. In vivo studies in a uPAR/LDLR double knockout mouse model of diet-induced atherosclerosis revealed impaired C5aR expression and calcification in aortic sinus plaques in uPAR -/ -/LDLR -/ -versus uPAR + / + /LDLR -/ -control animals. These results suggest that uPAR-C5aR axis via the underlying NFkB transcriptional program controls osteogenic differentiation with functional impact on vascular calcification in vivo.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 83%

Section: Fig 1 Mesenchymal Stem Cells (Msc) Undergo Differentiationmentioning

confidence: 92%

Section: Lentiviral Transfection and Nucleofectionmentioning

confidence: 99%

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Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Anaraki

Patecki²,

Larmann³

et al. 2014

Stem Cells and Development

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Mesenchymal stem/stromal cells alleviate early‐stage pulmonary fibrosis in a uPAR‐dependent manner

Efimenko,

Shmakova,

Popov

et al. 2024

Cell Biology International

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Pulmonary fibrosis, a debilitating lung disorder characterised by excessive fibrous tissue accumulation in lung parenchyma, compromises respiratory function leading to a life‐threatening respiratory failure. While its origins are multifaceted and poorly understood, the urokinase system, including urokinase‐type plasminogen activator (uPA) and its receptor (uPAR), plays a significant role in regulating fibrotic response, extracellular matrix remodelling, and tissue repair. Mesenchymal stem/stromal cells (MSCs) hold promise in regenerative medicine for treating pulmonary fibrosis. Our study aimed to investigate the potential of MSCs to inhibit pulmonary fibrosis as well as the contribution of uPAR expression to this effect. We found that intravenous MSC administration significantly reduced lung fibrosis in the bleomycin‐induced pulmonary fibrosis model in mice as revealed by MRI and histological evaluations. Notably, administering the MSCs isolated from adipose tissue of uPAR knockout mice (Plaur‐/‐ MSCs) attenuated lung fibrosis to a lesser extent as compared to WT MSCs. Collagen deposition, a hallmark of fibrosis, was markedly reduced in lungs treated with WT MSCs versus Plaur‐/‐ MSCs. Along with that, endogenous uPA levels were affected differently; after Plaur‐/‐ MSCs were administered, the uPA content was specifically decreased within the blood vessels. Our findings support the potential of MSC treatment in attenuating pulmonary fibrosis. We provide evidence that the observed anti‐fibrotic effect depends on uPAR expression in MSCs, suggesting that uPAR might counteract the uPA accumulation in lungs.

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Extracellular vesicles as carriers of microRNA, proteins and lipids in tumor microenvironment

et al. 2015

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In recent years, the knowledge about the control of tumor microenvironment has increased and emerged as an important player in tumorigenesis. The role of normal stromal cells in the tumor initiation and progression has brought our vision in to the forefront of cell-to-cell communication. In this review, we focus on the mechanism of communication between stromal and tumor cells, which is based on the exchange of extracellular vesicles (EVs). We describe several, evergrowing, pieces of evidence that EVs transfer messages through their miRNA, lipid, protein and nucleic acid contents. A better understanding of this sophisticated method of communication between normal cancer cells may lead to developing novel approaches for personalized diagnostics and therapeutics.

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Urokinase receptor mediates mobilization, migration, and differentiation of mesenchymal stem cells

Abstract: These data suggest a multifaceted function of uPAR in MSC biology contributing to vascular repair. uPAR might guide and control the trafficking of MSCs to the vascular wall in response to injury or ischaemia and their differentiation towards functional VSMCs at the site of arterial injury.

Cited by 47 publications

References 48 publications

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Mesenchymal stem/stromal cells alleviate early‐stage pulmonary fibrosis in a uPAR‐dependent manner

Extracellular vesicles as carriers of microRNA, proteins and lipids in tumor microenvironment

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