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Spontaneous In Vivo Chondrogenesis of Bone Marrow-Derived Mesenchymal Progenitor Cells by Blocking Vascular Endothelial Growth Factor Signaling

Marsano, Anna and Medeiros da Cunha, Carolina M. and Ghanaati, Shahram and Gueven, Sinan and Centola, Matteo and Tsaryk, Roman and Barbeck, Mike and Stuedle, Chiara and Barbero, Andrea and Helmrich, Uta and Schaeren, Stefan and Kirkpatrick, James C. and Banfi, Andrea and Martin, Ivan. (2016) Spontaneous In Vivo Chondrogenesis of Bone Marrow-Derived Mesenchymal Progenitor Cells by Blocking Vascular Endothelial Growth Factor Signaling. Stem Cells Translational Medicine, 5 (12). pp. 1730-1738.

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Abstract

Chondrogenic differentiation of bone marrow-derived mesenchymal stromal/stem cells (MSCs) can be induced by presenting morphogenetic factors or soluble signals but typically suffers from limited efficiency, reproducibility across primary batches, and maintenance of phenotypic stability. Considering the avascular and hypoxic milieu of articular cartilage, we hypothesized that sole inhibition of angiogenesis can provide physiological cues to direct in vivo differentiation of uncommitted MSCs to stable cartilage formation. Human MSCs were retrovirally transduced to express a decoy soluble vascular endothelial growth factor (VEGF) receptor-2 (sFlk1), which efficiently sequesters endogenous VEGF in vivo, seeded on collagen sponges and immediately implanted ectopically in nude mice. Although naïve cells formed vascularized fibrous tissue, sFlk1-MSCs abolished vascular ingrowth into engineered constructs, which efficiently and reproducibly developed into hyaline cartilage. The generated cartilage was phenotypically stable and showed no sign of hypertrophic evolution up to 12 weeks. In vitro analyses indicated that spontaneous chondrogenic differentiation by blockade of angiogenesis was related to the generation of a hypoxic environment, in turn activating the transforming growth factor-β pathway. These findings suggest that VEGF blockade is a robust strategy to enhance cartilage repair by endogenous or grafted mesenchymal progenitors. This article outlines the general paradigm of controlling the fate of implanted stem/progenitor cells by engineering their ability to establish specific microenvironmental conditions rather than directly providing individual morphogenic cues.; Chondrogenic differentiation of mesenchymal stromal/stem cells (MSCs) is typically targeted by morphogen delivery, which is often associated with limited efficiency, stability, and robustness. This article proposes a strategy to engineer MSCs with the capacity to establish specific microenvironmental conditions, supporting their own targeted differentiation program. Sole blockade of angiogenesis mediated by transduction for sFlk-1, without delivery of additional morphogens, is sufficient for inducing MSC chondrogenic differentiation. The findings represent a relevant step forward in the field because the method allowed reducing interdonor variability in MSC differentiation efficiency and, importantly, onset of a stable, nonhypertrophic chondrocyte phenotype.
Faculties and Departments:03 Faculty of Medicine > Bereich Operative Fächer (Klinik) > Querschnittsbereich Forschung > Tissue Engineering (Martin)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Operative Fächer (Klinik) > Querschnittsbereich Forschung > Tissue Engineering (Martin)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Cardiac Surgery and Engineering (Marsano)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Cell and Gene Therapy (Banfi)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Tissue Engineering (Martin)
UniBasel Contributors:Marsano, Anna and Martin, Ivan and Banfi, Andrea
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Wiley
ISSN:2157-6564
e-ISSN:2157-6580
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:08 Jun 2018 14:31
Deposited On:03 Oct 2017 07:44

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