Transgene-activated mesenchymal cells for articular cartilage repair: a comparison of primary bone marrow-, perichondrium/periosteum- and fat-derived cells

Park, Jung; Gelse, Kolja; Frank, Susi K.; Mark, Klaus von der; Aigner, Thomas; Schneider, Holm

doi:10.1002/jgm.826

Cited by 123 publications

(88 citation statements)

References 49 publications

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“…As observed in our recent studies on rats (14,19), viral BMP-2 gene transfer efficiently induced chondrogenic differentiation of periosteal cells within 6 weeks. AAV vectors are known to facilitate long-term transgene expression; yet, their infection efficacy is relatively low and the onset of transgene expression is typically delayed (36).…”

Section: Discussionsupporting

confidence: 81%

Cell‐based resurfacing of large cartilage defects: Long‐term evaluation of grafts from autologous transgene‐activated periosteal cells in a porcine model of osteoarthritis

Gelse¹,

Mühle²,

Franke³

et al. 2008

Arthritis & Rheumatism

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Objective. To investigate the potential of transgene-activated periosteal cells for permanently resurfacing large partial-thickness cartilage defects.Methods. In miniature pigs, autologous periosteal cells stimulated ex vivo by bone morphogenetic protein 2 gene transfer, using liposomes or a combination of adeno-associated virus (AAV) and adenovirus (Ad) vectors, were applied on a bioresorbable scaffold to chondral lesions comprising the entire medial half of the patella. The resulting repair tissue was assessed, 6 and 26 weeks after transplantation, by histochemical and immunohistochemical methods. The biomechanical properties of the repair tissue were characterized by nanoindentation measurements. Implants of unstimulated cells and untreated lesions served as controls.Results. All grafts showed satisfactory integration into the preexisting cartilage. Six weeks after transplantation, AAV/Ad-stimulated periosteal cells had adopted a chondrocyte-like phenotype in all layers; the newly formed matrix was rich in proteoglycans and type II collagen, and its contact stiffness was close to that of healthy hyaline cartilage. Unstimulated periosteal cells and cells activated by liposomal gene transfer formed only fibrocartilaginous repair tissue with minor contact stiffness. However, within 6 months following transplantation, the AAV/Ad-stimulated cells in the superficial zone tended to dedifferentiate, as indicated by a switch from type II to type I collagen synthesis and reduced contact stiffness. In deeper zones, these cells retained their chondrocytic phenotype, coinciding with positive staining for type II collagen in the matrix.Conclusion. Large partial-thickness cartilage defects can be resurfaced efficiently with hyaline-like cartilage formed by transgene-activated periosteal cells. The long-term stability of the cartilage seems to depend on physicobiochemical factors that are active only in deeper zones of the cartilaginous tissue.

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Section: Discussionsupporting

confidence: 81%

Cell‐based resurfacing of large cartilage defects: Long‐term evaluation of grafts from autologous transgene‐activated periosteal cells in a porcine model of osteoarthritis

Gelse¹,

Mühle²,

Franke³

et al. 2008

Arthritis & Rheumatism

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“…MSCs have captured tremendous attention as a cell source alternative to chondrocytes and in vitro chondrogenesis of MSCs via the adenovirus-mediated BMP-2 expression and pellet culture has been demonstrated. 38,39 In comparison with adenovirus, which results in cytotoxicity at high MOI 38,40 and induces immune responses in vitro and in vivo, 2,6 baculovirus is generally considered safe with barely detectable viral protein expression and negligible cytotoxicity in the transduced mammalian cells. 8,10,40 Therefore, one may transduce the MSCs with BMP-2-expressing baculovirus and culture the cell/scaffold constructs in the RSB to initiate chondrogenesis.…”

Section: Discussionmentioning

confidence: 99%

Combination of baculovirus-expressed BMP-2 and rotating-shaft bioreactor culture synergistically enhances cartilage formation

et al. 2007

Gene Ther

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Baculovirus is an emerging gene delivery vector, thanks to a number of unique advantages. Herein, we genetically modified the rabbit articular chondrocytes with a recombinant baculovirus (Bac-CB) encoding bone morphogenetic protein-2 (BMP-2), which conferred high level BMP-2 expression and triggered the re-differentiation of dedifferentiated third passage (P3) chondrocytes in the monolayer culture. The transduced and mock-transduced P3 cells were seeded into porous scaffolds and cultured in either the dishes or the rotating-shaft bioreactor (RSB), a novel bioreactor imparting a dynamic, two-phase culture environment. Neither mocktransduced constructs in the RSB culture nor the Bac-CBtransduced constructs in the static culture grew into uniform cartilaginous tissues. Only the Bac-CB-transduced constructs cultured in the RSB for 3 weeks resulted in cartilaginous tissues with hyaline appearance, uniform cell distribution, cartilage-specific gene expression and considerably enhanced cartilage-specific extracellular matrix deposition, as determined by histological staining, reverse transcription-PCR analyses and biochemical assays. This is the first study demonstrating that combination of baculovirusmediated growth factor expression and RSB culture synergistically enhanced in vitro creation of cartilaginous tissues from dedifferentiated chondrocytes. Since baculovirus transduction is generally considered safe, this approach represents a viable alternative to stimulate the formation of engineered cartilage in a more cost-effective way than the growth factor supplementation.

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“…More than 50 adenovirus serotypes are available for gene therapy and serotype 5 (Ad5) has been the mostly used in both in vitro and in vivo studies. Adenovirus is used to transfer GF genes (TGF-β, FGF-2, IGF-1, BMPs and Growth and differentiation factor 5, GDF-5) into cells [8,20,25,[40][41][42][43][44][45][46][47][48][49]. Genes, in encapsuled viral [24] vector, can be injected directly in vivo [50,51] or through decalcified cortical bone matrix (DCBM) as scaffold that contains the viral particles [52].…”

Section: Viral Vectormentioning

confidence: 99%

Gene therapy for chondral and osteochondral regeneration: is the future now?

Bellavia

Veronesi

Carina

et al. 2017

Cell. Mol. Life Sci.

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Gene therapy might represent a promising strategy for chondral and osteochondral defects repair by balancing the management of temporary joint mechanical incompetence with altered metabolic and inflammatory homeostasis. This review analysed preclinical and clinical studies on gene therapy for the repair of articular cartilage defects performed over the last 10 years, focussing on expression vectors (non-viral and viral), type of genes delivered and gene therapy procedures (direct or indirect). Plasmids (non-viral expression vectors) and adenovirus (viral vectors) were the most employed vectors in preclinical studies. Genes delivered encoded mainly for growth factors, followed by transcription factors, anti-inflammatory cytokines and, less frequently, by cell signalling proteins, matrix proteins and receptors. Direct injection of the expression vector was used less than indirect injection of cells, with or without scaffolds, transduced with genes of interest and then implanted into the lesion site. Clinical trials (phases I, II or III) on safety, biological activity, efficacy, toxicity or bio-distribution employed adenovirus viral vectors to deliver growth factors or anti-inflammatory cytokines, for the treatment of osteoarthritis or degenerative arthritis, and tumour necrosis factor receptor or interferon for the treatment of inflammatory arthritis

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Transgene-activated mesenchymal cells for articular cartilage repair: a comparison of primary bone marrow-, perichondrium/periosteum- and fat-derived cells

Abstract: Perichondrium/periosteum-derived cells and BMSC seem superior to cells isolated from fat with respect to forming hyaline cartilaginous tissue. A chondrogenic stimulus, e.g. by transfer of BMP-2 cDNA, appears to be required for initiation and support of chondrogenic differentiation.

Cited by 123 publications

References 49 publications

Cell‐based resurfacing of large cartilage defects: Long‐term evaluation of grafts from autologous transgene‐activated periosteal cells in a porcine model of osteoarthritis

Cell‐based resurfacing of large cartilage defects: Long‐term evaluation of grafts from autologous transgene‐activated periosteal cells in a porcine model of osteoarthritis

Combination of baculovirus-expressed BMP-2 and rotating-shaft bioreactor culture synergistically enhances cartilage formation

Gene therapy for chondral and osteochondral regeneration: is the future now?

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