Effect of Lumican on the Migration of Human Mesenchymal Stem Cells and Endothelial Progenitor Cells: Involvement of Matrix Metalloproteinase-14

Malinowski, Mariusz; Pietraszek, Katarzyna; Perreau, Corinne; Mateusz, Boguslawski; Decot, Véronique; Stoltz, Jean‐François; Vallar, Laurent; Niewiarowska, Jolanta; Cierniewski, Czesław S.; Maquart, François‐Xavier; Wegrowski, Yanusz; Brézillon, Stéphane

doi:10.1371/journal.pone.0050709

Cited by 45 publications

(37 citation statements)

References 49 publications

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“…We have thus demonstrated, for the first time, that MMP14 is a possible downstream target of activated VEGFR2 in migratory NSCs. This finding is in agreement with previously published data that showed that decreased MMP14 activity inhibited the migration of human bone marrow MSCs 48 . The same study also revealed that MMP14 overexpression had the capacity to restore MSC migration.…”

Section: Discussionsupporting

confidence: 94%

MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells

et al. 2015

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Neural stem cell (NSC)-based carriers have been presented as promising therapeutic tools for the treatment of infiltrative brain tumors due to their intrinsic tumor homing properties. They have demonstrated the ability to migrate towards distant tumor microsatellites and effectively deliver the therapeutic payload, thus significantly improving survival in experimental animal models for brain tumors. Despite such optimistic results, the efficacy of NSC-based anti-cancer therapy has been limited due to the restricted tumor homing ability of NSCs. To examine this issue, we investigated the mechanisms of tumor-tropic migration of an FDA-approved NSC line, HB1.F3.CD, by performing a gene expression analysis. We identified vascular endothelial growth factor-A (VEGFA) and membrane-bound matrix metalloproteinase (MMP14) as molecules whose expressions are significantly elevated in migratory NSCs. We observed increased expression of VEGF receptor 2 (VEGFR2) in the focal adhesion complexes of migratory NSCs, with downstream activation of VEGFR2-dependent kinases such as p-PLCγ, p-FAK, and p-Akt, a signaling cascade reported to be required for cellular migration. In an in vivo orthotopic glioma xenograft model, analysis of the migratory trail showed that NSCs maintained expression of VEGFR2 and preferentially migrated within the perivascular space. Knockdown of VEGFR2 via shRNAs led to significant downregulation of MMP14 expression, which resulted in inhibited tumor-tropic migration. Overall, our results suggest, for the first time, the involvement of VEGFR2-regulated MMP14 in the tumor-tropic migratory behavior of NSCs. Our data warrant investigation of MMP14 as a target for enhancing the migratory properties of NSC carriers and optimizing the delivery of therapeutic payloads to disseminated tumor burdens.

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Section: Discussionsupporting

confidence: 94%

MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells

et al. 2015

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“…Although bone marrow MSCs form a tubule network when cultured on Matrigel [38,39], thymus MSCs tended to cluster together to form microcellular aggregates on fibrin hydrogel. This different behavior may be attributable to Figure 5.…”

Section: Discussionmentioning

confidence: 99%

Characterization and Angiogenic Potential of Human Neonatal and Infant Thymus Mesenchymal Stromal Cells

Wang

Mundada

Johnson

et al. 2015

Stem Cells Translational Medicine

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Mesenchymal stromal cells (MSCs) are present in large numbers in discarded neonatal and infant thymus tissue and can be isolated by an explant culture method. Explant culture‐isolated thymus MSCs demonstrate the classical characteristics of bone marrow MSCs. Thymus MSCs also possess proangiogenic qualities and deserve further consideration as a potential cell therapeutic agent to promote tissue regeneration and repair and for use in strategies to vascularize engineered tissues.

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“…Lumican inhibits in vitro tube-like structure formation by bone marrow-derived MSCs via downregulation of MT1-MMP expression and activity in MSCs, and overexpression of MT1-MMP enhances MSC migration and invasion [69]. …”

Section: Mmps Stem/progenitor Cell Mobilization Recruitment Andmentioning

confidence: 99%

Matrix Metalloproteinases: Inflammatory Regulators of Cell Behaviors in Vascular Formation and Remodeling

Chen

Jin

Yang

et al. 2013

Mediators of Inflammation

384

307

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Abnormal angiogenesis and vascular remodeling contribute to pathogenesis of a number of disorders such as tumor, arthritis, atherosclerosis, restenosis, hypertension, and neurodegeneration. During angiogenesis and vascular remodeling, behaviors of stem/progenitor cells, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs) and its interaction with extracellular matrix (ECM) play a critical role in the processes. Matrix metalloproteinases (MMPs), well-known inflammatory mediators are a family of zinc-dependent proteolytic enzymes that degrade various components of ECM and non-ECM molecules mediating tissue remodeling in both physiological and pathological processes. MMPs including MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MT1-MMP, are stimulated and activated by various stimuli in vascular tissues. Once activated, MMPs degrade ECM proteins or other related signal molecules to promote recruitment of stem/progenitor cells and facilitate migration and invasion of ECs and VSMCs. Moreover, vascular cell proliferation and apoptosis can also be regulated by MMPs via proteolytically cleaving and modulating bioactive molecules and relevant signaling pathways. Regarding the importance of vascular cells in abnormal angiogenesis and vascular remodeling, regulation of vascular cell behaviors through modulating expression and activation of MMPs shows therapeutic potential.

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Effect of Lumican on the Migration of Human Mesenchymal Stem Cells and Endothelial Progenitor Cells: Involvement of Matrix Metalloproteinase-14

Cited by 45 publications

References 49 publications

MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells

MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells

Characterization and Angiogenic Potential of Human Neonatal and Infant Thymus Mesenchymal Stromal Cells

Matrix Metalloproteinases: Inflammatory Regulators of Cell Behaviors in Vascular Formation and Remodeling

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