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Dive into the research topics where Francesco Dell'Accio is active.

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Featured researches published by Francesco Dell'Accio.


Arthritis & Rheumatism | 2001

Multipotent mesenchymal stem cells from adult human synovial membrane

Cosimo De Bari; Francesco Dell'Accio; Przemyslaw Tylzanowski; Frank P. Luyten

OBJECTIVE To characterize mesenchymal stem cells (MSCs) from human synovial membrane (SM). METHODS Cell populations were enzymatically released from the SM obtained from knee joints of adult human donors and were expanded in monolayer with serial passages at confluence. Cell clones were obtained by limiting dilution. At different passages, SM-derived cells were subjected to in vitro assays to investigate their multilineage potential. Upon treatments, phenotypes of cell cultures were analyzed by histo- and immunohistochemistry and by semiquantitative reverse transcription-polymerase chain reaction for the expression of lineage-retated marker genes. RESULTS SM-derived cells could be expanded extensively in monolayer, with limited senescence. Under appropriate culture conditions, SM-derived cells were induced to differentiate to the chondrocyte, osteocyte, and adipocyte lineages. Sporadic myogenesis was also observed. Five independent cell clones displayed multilineage potential. Interestingly, only 1 clone was myogenic. Donor age, cell passaging, and cryopreservation did not affect the multilineage potential of SM-derived cells. In contrast, normal dermal fibroblasts under the same culture conditions did not display this potential. CONCLUSION Our study demonstrates that human multipotent MSCs can be isolated from the SM of knee joints. These cells have the ability to proliferate extensively in culture, and they maintain their multilineage differentiation potential in vitro, establishing their progenitor cell nature. SM-derived MSCs may play a role in the regenerative response during arthritic diseases and are promising candidates for developing novel cell-based therapeutic approaches for postnatal skeletal tissue repair.


Arthritis & Rheumatism | 2001

Human periosteum-derived cells maintain phenotypic stability and chondrogenic potential throughout expansion regardless of donor age

Cosimo De Bari; Francesco Dell'Accio; Frank P. Luyten

OBJECTIVE To assess the in vitro chondrogenic potential of adult human periosteum-derived cells (PDCs) with regard to the number of cell passages and the age of the donor. METHODS Cells were enzymatically released from the periosteum of the proximal tibia obtained from adult human donors and expanded in monolayer. PDCs were harvested at multiple passages for total RNA extraction and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) gene expression analysis. For the chondrogenesis assay, cells were plated in micromass and treated with transforming growth factor beta1 (TGFbeta1) in a chemically defined medium. At different time points, micromasses were either harvested for RT-PCR analysis for cartilage and bone markers or fixed, paraffin-embedded, and stained for cartilage matrix, and immunostained for type II collagen. RESULTS At the first 2 passages, human PDCs from young donors formed chondrogenic nodules. This spontaneous chondrogenic activity was lost upon passaging, and it was not observed in donors older than 30 years. Using a panel of marker genes, PDCs were shown to be phenotypically stable during cell expansion. Regardless of donor age or cell passage, chondrogenesis could be induced consistently by combining micromass culture and TGFbeta1 treatment. Histochemical and immunohistochemical analyses demonstrated the hyaline-like cartilage phenotype of the tissue generated in vitro. Other TGFbeta superfamily members, such as growth differentiation factor 5/cartilage-derived morphogenetic protein 1, and bone morphogenetic proteins 2, 4, and 7, were poorly chondrogenic under the same culture conditions. CONCLUSION Adult human PDCs have the potential to differentiate toward the chondrocytic lineage in vitro, retaining this property even after extensive subculture. Human PDCs are easily accessible, expandable, and maintain their chondrogenic potential, and are therefore promising progenitor cells for use in the repair of joint surface defects.


Arthritis & Rheumatism | 2001

Molecular markers predictive of the capacity of expanded human articular chondrocytes to form stable cartilage in vivo

Francesco Dell'Accio; Cosimo De Bari; Frank P. Luyten

OBJECTIVE To establish a model and associated molecular markers for monitoring the capacity of in vitro-expanded chondrocytes to generate stable cartilage in vivo. METHODS Adult human articular chondrocytes (AHAC) were prepared by collagenase digestion of samples obtained postmortem and were expanded in monolayer. Upon passaging, aliquots of chondrocyte suspensions were either injected intramuscularly into nude mice, cultured in agarose, or used for gene expression analysis. Cartilage formation in vivo was documented by histology, histochemistry, immunofluorescence for type II collagen, and proteoglycan analysis by 35S-sulfate incorporation and molecular sieve chromatography of the radiolabeled macromolecules. In situ hybridization for species-specific genomic repeats was used to discriminate human-derived from mouse-derived cells. Gene expression dynamics were analyzed by semiquantitative reverse transcription-polymerase chain reaction. RESULTS Intramuscular injection of freshly isolated AHAC into nude mice resulted in stable cartilage implants that were resistant to mineralization, vascular invasion, and replacement by bone. In vitro expansion of AHAC resulted in the loss of in vivo cartilage formation. This capacity was positively associated with the expression of fibroblast growth factor receptor 3, bone morphogenetic protein 2, and alpha1(II) collagen (COL2A1), and its loss was marked by the up-regulation of activin receptor-like kinase 1 messenger RNA. Anchorage-independent growth and the reexpression of COL2A1 in agarose culture were insufficient to predict cartilage formation in vivo. CONCLUSION AHAC have a finite capacity to form stable cartilage in vivo; this capacity is lost throughout passaging and can be monitored using a nude mouse model and associated molecular markers. This cartilage-forming ability in vivo may be pivotal for successful cell-based joint surface defect repair protocols.


Journal of Orthopaedic Research | 2003

Expanded phenotypically stable chondrocytes persist in the repair tissue and contribute to cartilage matrix formation and structural integration in a goat model of autologous chondrocyte implantation

Francesco Dell'Accio; Johan Vanlauwe; Johan Bellemans; Johan Neys; Cosimo De Bari; Frank P. Luyten

Autologous chondrocyte implantation (ACI) is an established technique to repair joint surface defects. Although there is some indirect evidence that the expanded chondrocytes are required to achieve proper healing, the role they play in the repair process is not clear yet. To monitor the persistence and the phenotype of the injected chondrocytes in the repair tissue (RT) we have optimized a fluorescent labeling protocol for articular chondrocytes, which allows cell tracking in vivo for up to 14 weeks, using the fluorescent dye PKH26. We have combined in vivo cell tracking, with the immune‐detection of collagen type II protein in a goat model of ACI. Our data indicate that the implanted cells can persist for at least 14 weeks in the defects, can participate in the integration with the surrounding tissues, and become structural part of the RT, rich in collagen type II and sulfated proteoglycans. Albeit with a small number of samples, our data provide proof of principal that the implanted chondrocytes can contribute to structural cartilage repair in a goat model of ACI.


Arthritis & Rheumatism | 2008

Identification of the molecular response of articular cartilage to injury, by microarray screening: Wnt‐16 expression and signaling after injury and in osteoarthritis

Francesco Dell'Accio; Cosimo De Bari; N.M. Eltawil; Paul Vanhummelen; Costantino Pitzalis

OBJECTIVE To characterize the molecular response of adult human articular cartilage to acute mechanical injury. METHODS An established ex vivo model was used to compare gene expression of adult human articular cartilage explants 24 hours after mechanical injury with that of uninjured controls by microarray analysis of gene expression. Confirmation for selected genes was obtained by real-time polymerase chain reaction and immunohistochemical analysis. Expression of selected genes was also investigated in preserved and osteoarthritic (OA) cartilage. RESULTS Six hundred ninety genes were significantly regulated at least 2-fold following mechanical injury. They included genes previously reported to be differentially expressed in OA versus normal cartilage or having allelic variants genetically linked to OA. Significant functional clusters included genes associated with wound healing, developmental processes, and skeletal development. The transforming growth factor beta, fibroblast growth factor, and Wnt pathways were modulated. A systematic analysis of the Wnt signaling pathway revealed up-regulation of Wnt-16, down-regulation of FRZB, up-regulation of Wnt target genes, and nuclear localization of beta-catenin in injured cartilage. In addition, in OA, Wnt-16 and beta-catenin were barely detectable in preserved cartilage areas, but were dramatically up-regulated in areas of the same joint with moderate to severe OA damage. CONCLUSION Our findings indicate that mechanical injury to adult human articular cartilage results in the activation of a signaling response, with reactivation of morphogenetic pathways. Therapeutic targeting of such pathways may improve current protocols of joint surface defect repair and/or prevent the evolution of such lesions into posttraumatic OA.


Arthritis & Rheumatism | 2011

Functional Mesenchymal Stem Cell Niches in Adult Mouse Knee Joint Synovium In Vivo

Tobias Kurth; Francesco Dell'Accio; Vicki Crouch; Andrea Augello; Paul T. Sharpe; Cosimo De Bari

OBJECTIVE We previously reported that human synovium contains cells that, after culture expansion, display properties of mesenchymal stem cells (MSCs). The objective of this study was to identify MSCs in native synovium in vivo. METHODS To identify stem cells in the synovium in vivo, a double nucleoside analog cell-labeling scheme was used in a mouse model of joint-surface injury. For labeling of slow-cycling cells, mice received iododeoxyuridine (IdU) for 30 days, followed by a 40-day washout period. For labeling of cells that proliferate after injury, mice underwent knee surgery to produce an articular cartilage defect and received chlorodeoxyuridine (CIdU) for 4 days, starting at multiple time points after surgery. Unoperated and sham-operated joints served as controls. Knee joint paraffin sections were analyzed by double and triple immunostaining to detect nucleoside analogs, conventional MSC markers, and chondrocyte-lineage markers. RESULTS Long-term-retaining, slow-cycling IdU-positive cells were detected in the synovium. At 4 days and 8 days after injury, there was marked proliferation of IdU-positive cells, which costained for CIdU. IdU-positive cells were nonhematopoietic, nonendothelial stromal cells, were distinct from pericytes, and stained positive for MSC markers. MSCs were phenotypically heterogeneous and located in topographically distinct niches in the lining layer and the subsynovial tissue. Twelve days after injury, double nucleoside-labeled cells within synovium were embedded in cartilage-specific metachromatic extracellular matrix and costained positive for the chondrocyte-lineage markers Sox9 and type II collagen. CONCLUSION Our findings provide the first evidence of the existence of resident MSCs in the knee joint synovium that undergo proliferation and chondrogenic differentiation following injury in vivo.


Arthritis Research & Therapy | 2006

Activation of WNT and BMP signaling in adult human articular cartilage following mechanical injury

Francesco Dell'Accio; Cosimo De Bari; Noha M F El Tawil; Francesca Barone; Thimios A. Mitsiadis; John O'Dowd; Costantino Pitzalis

Acute full thickness joint surface defects can undergo repair, which involves tissue patterning and endochondral bone formation. Molecular signals regulating this process may contribute to the repair outcome, chronic evolution and, eventually, the onset of osteoarthritis. We tested the hypothesis that mechanical injury modulates morphogenetic pathways in adult human articular cartilage explants. Adjacent articular cartilage explants were obtained from preserved areas of the femoral condyles of patients undergoing arthroplasty for osteoarthritis, or from a normal joint of a patient undergoing lower limb amputation. Paired explants were individually maintained in explant culture. From each pair, one explant was mechanically injured and the other left uninjured as a control. Cultures were terminated at different time points for histochemistry, immunohistochemistry and gene expression analysis by reverse transcription real time PCR. Bone morphogenetic protein 2 (BMP-2) mRNA was upregulated in the injured explants. We detected phosphorylation of SMAD-1 and SMAD-5, consistent with activation of the bone morphogenetic protein (BMP) pathway. FRZB-1 mRNA was downregulated in the injured explants, suggesting de-repression of WNT signaling. Accordingly, expression of the canonical WNT target genes Axin-2 and c-JUN was upregulated in the injured explants. Activation of the canonical WNT signaling pathway by LiCl treatment induced upregulation of COL2A1 and Aggrecan mRNA, suggesting an anabolic effect. Phosphorylation of SMAD-1/-5 and downregulation of FRZB were confirmed in vivo in a mouse model of joint surface injury. Taken together, these data show modulation of the BMP and WNT pathways following mechanical injury in vitro and in vivo, which may play a role in the reparative response of the joint surface. These pathways may, therefore, represent potential targets in protocols of biological joint surface defect repair.


Journal of Cell Biology | 2011

WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways

G. Nalesso; J. Sherwood; Jessica Bertrand; Thomas Pap; Cosimo De Bari; Costantino Pitzalis; Francesco Dell'Accio

A single Wnt can simultaneously activate different pathways with distinct and independent outcomes and reciprocal regulation in human articular chondrocytes.


Experimental Cell Research | 2003

Microenvironment and phenotypic stability specify tissue formation by human articular cartilage-derived cells in vivo

Francesco Dell'Accio; Cosimo De Bari; Frank P. Luyten

During in vitro expansion, adult human articular cartilage-derived cells (HACDC) lose their phenotypic stability and capacity to form cartilage in vivo after 4-6 population doublings (PD). Nevertheless, HACDC can be efficiently expanded for up to 20 PD. Here we show that HACDC can generate cartilage, fibrous tissue, skeletal muscle, bone, and adipocytes depending on the balance between phenotypic stability and environmental cues. When 5 x 10(6) cells were injected intramuscularly into nude mice, early-passage (EP)-HACDC formed cartilage; late-passage (LP)-HACDC formed mostly fibrous tissue, but a limited number of cells contributed to muscle formation. When 0.5 x 10(6) cells were injected into regenerating mouse muscle, both EP- and LP-HACDC integrated with host myofibers and expressed muscle genes, but a number of EP-HACDC maintained collagen type II expression. HACDC seeded into Collagraft and implanted subcutaneously into nude mice formed scattered bone islands displaying immunoreactivity for human osteocalcin, and expressing human bone-specific genes. Importantly, neither collagen type II transcript nor cartilage tissue was detected at 8 weeks after implantation. Myogenic, osteogenic, and adipogenic differentiation was induced in vitro using specific culture conditions. These findings provide evidence that in vivo tissue formation by HACDC is specified by a balance between environmental cues and the inherent phenotypic stability.


Arthritis & Rheumatism | 2008

A biomarker-based mathematical model to predict bone-forming potency of human synovial and periosteal mesenchymal stem cells.

Cosimo De Bari; Francesco Dell'Accio; Alexandra Karystinou; Pascale V. Guillot; Nicholas M. Fisk; Elena Jones; Dennis McGonagle; Ilyas M. Khan; Charles William Archer; Thimios A. Mitsiadis; Ana Nora Donaldson; Frank P. Luyten; Costantino Pitzalis

OBJECTIVE To develop a biomarker-based model to predict osteogenic potency of human mesenchymal stem cells (MSCs) from synovial membrane and periosteum. METHODS MSC populations were derived from adult synovium and periosteum. Phenotype analysis was performed by fluorescence-activated cell sorting and real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Telomere lengths were determined by Southern blot analysis. In vitro osteogenesis was assessed quantitatively by measurements of alkaline phosphatase activity and calcium deposits. To investigate bone formation in vivo, MSCs were seeded onto osteoinductive scaffolds and implanted subcutaneously in nude mice. Bone was assessed by histology, and the human origin investigated by in situ hybridization for human Alu genomic repeats. Quantitation was achieved by histomorphometry and real-time RT-PCR for human osteocalcin. Analysis at the single-cell level was performed with clonal populations obtained by limiting dilution. Multiple regressions were used to explore the incremental predictive value of the markers. RESULTS Periosteal MSCs had significantly greater osteogenic potency than did synovial MSCs inherent to the single cell. Bone was largely of human origin in vivo. Within the same tissue type, there was variability between different donors. To identify predictors of osteogenic potency, we measured the expression levels of osteoblast lineage genes in synovial and periosteal clonal MSCs prior to osteogenic treatment. We identified biomarkers that correlated with osteogenic outcome and developed a mathematical model based on type I collagen and osteoprotegerin expression that predicts the bone-forming potency of MSC preparations, independent of donor-related variables and tissue source. CONCLUSION Our findings indicate that our quality-control mathematical model estimates the bone-forming potency of MSC preparations for bone repair.

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Frank P. Luyten

Katholieke Universiteit Leuven

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Costantino Pitzalis

Queen Mary University of London

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G. Nalesso

Queen Mary University of London

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J. Sherwood

Queen Mary University of London

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Jessica Bertrand

Otto-von-Guericke University Magdeburg

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Thomas Pap

University of Münster

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C. De Bari

University of Aberdeen

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S.E. Eldridge

Queen Mary University of London

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Bari Cosimo De

Katholieke Universiteit Leuven

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