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Blocking vascular endothelial growth factor with soluble Flt-1 improves the chondrogenic potential of mouse skeletal muscle-derived stem cells

Kubo, S and Cooper, GM and Matsumoto, T and Phillippi, JA and Corsi, KA and Usas, A and Li, G and Fu, FH and Huard, J (2009) Blocking vascular endothelial growth factor with soluble Flt-1 improves the chondrogenic potential of mouse skeletal muscle-derived stem cells. Arthritis and Rheumatism, 60 (1). 155 - 165. ISSN 0004-3591

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Objective. To investigate the effect of vascular endothelial growth factor (VEGF) stimulation and the effect of blocking VEGF with its antagonist, soluble Flt-1 (sFlt-1), on chondrogenesis, using muscle-derived stem cells (MDSCs) isolated from mouse skeletal muscle. Methods. The direct effect of VEGF on the in vitro chondrogenic ability of mouse MDSCs was tested using a pellet culture system, followed by real-time quantitative polymerase chain reaction (PCR) and histologic analyses. Next, the effect of VEGF on chondrogenesis within the synovial joint was tested, using genetically engineered MDSCs implanted into rat osteochondral defects. In this model, MDSCs transduced with a retroviral vector to express bone morphogenetic protein 4 (BMP-4) were coimplanted with MDSCs transduced to express either VEGF or sFlt-1 (a VEGF antagonist) to provide a gain- and loss-of-function experimental design. Histologic scoring was used to compare cartilage formation among the treatment groups. Results. Hyaline-like cartilage matrix production was observed in both VEGF-treated and VEGF-blocked (sFlt-1-treated) pellet cultures, but quantitative PCR revealed that sFlt-1 treatment improved the expression of chondrogenic genes in MDSCs that were stimulated to undergo chondrogenic differentiation with BMP-4 and transforming growth factor β3 (TGFβ3). In vivo testing of articular cartilage repair showed that VEGF-transduced MDSCs caused an arthritic change in the knee joint, and sFlt-1 improved the MDSC-mediated repair of articular cartilage, compared with BMP-4 alone. Conclusion. Soluble Flt-1 gene therapy improved the BMP-4- and TGFβ3-induced chondrogenic gene expression of MDSCs in vitro and improved the persistence of articular cartilage repair by preventing vascularization and bone invasion into the repaired articular cartilage. © 2009, American College of Rheumatology.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Kubo, S
Cooper, GMgmc8@pitt.eduGMC8
Matsumoto, T
Phillippi, JAjap103@pitt.eduJAP103
Corsi, KA
Usas, A
Li, G
Fu, FHffu@pitt.eduFFU
Huard, J
Date: 1 January 2009
Date Type: Publication
Journal or Publication Title: Arthritis and Rheumatism
Volume: 60
Number: 1
Page Range: 155 - 165
DOI or Unique Handle: 10.1002/art.24153
Schools and Programs: School of Medicine > Pediatrics
Refereed: Yes
ISSN: 0004-3591
MeSH Headings: Animals; Bone Morphogenetic Protein 4--genetics; Cartilage, Articular--cytology; Cell Differentiation--physiology; Cells, Cultured; Chondrogenesis--physiology; Genetic Therapy--methods; Hyaline Cartilage--cytology; Indicators and Reagents; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal--cytology; Osteoarthritis, Knee--pathology; Osteoarthritis, Knee--physiopathology; Osteoarthritis, Knee--therapy; Phenazines; Rats; Rats, Nude; Solubility; Stem Cell Transplantation; Stem Cells--physiology; Transduction, Genetic; Vascular Endothelial Growth Factor A--antagonists & inhibitors; Vascular Endothelial Growth Factor A--genetics; Vascular Endothelial Growth Factor A--metabolism; Vascular Endothelial Growth Factor Receptor-1--genetics; Vascular Endothelial Growth Factor Receptor-1--metabolism
Other ID: NLM NIHMS239028, NLM PMC3075626
PubMed Central ID: PMC3075626
PubMed ID: 19116905
Date Deposited: 09 Apr 2014 16:36
Last Modified: 02 Feb 2019 16:58


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