title: Spontaneous In Vivo Chondrogenesis of Bone Marrow-Derived Mesenchymal Progenitor Cells by Blocking Vascular Endothelial Growth Factor Signaling.
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.
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.|Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Marsano
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.|Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Medeiros da Cunha
authors.affiliation: Institute of Pathology, University Medical Center Mainz, Mainz, Germany.|Department for Oral, Craniomaxillofacial and Facial Plastic Surgery, University Frankfurt am Main, Frankfurt, Germany.
authors.forename: Shahram
authors.initials: S
authors.lastname: Ghanaati
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.|Department of Surgery, University Hospital Basel, Basel, Switzerland.|Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey.
authors.forename: Sinan
authors.initials: S
authors.lastname: Gueven
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.|Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Matteo
authors.initials: M
authors.lastname: Centola
authors.affiliation: Institute of Pathology, University Medical Center Mainz, Mainz, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Tsaryk
authors.affiliation: Institute of Pathology, University Medical Center Mainz, Mainz, Germany.|Department for Oral, Craniomaxillofacial and Facial Plastic Surgery, University Frankfurt am Main, Frankfurt, Germany.
authors.forename: Mike
authors.initials: M
authors.lastname: Barbeck
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.|Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Stuedle
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.|Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Barbero
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.|Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Uta
authors.initials: U
authors.lastname: Helmrich
authors.affiliation: Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schaeren
authors.affiliation: Institute of Pathology, University Medical Center Mainz, Mainz, Germany.
authors.forename: James C
authors.initials: JC
authors.lastname: Kirkpatrick
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland ivan.martin@usb.ch Andrea.Banfi@usb.ch.|Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Banfi
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland ivan.martin@usb.ch Andrea.Banfi@usb.ch.|Department of Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Martin
mesh_terms: D000328:Adult; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020219:Chondrogenesis / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D006984:Hypertrophy; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D055815:Young Adult
chemical_list: D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D010100:Oxygen
keywords: Chondrogenesis; Hypoxia; Mesenchymal stromal/stem cells; Vascular endothelial growth factor blockade