Jiménez, G.López-Ruiz, E.Kwiatkowski, W.Montañez, E.Arrebola, F.Carrillo, E.Gray, P. C.Izpisua Belmonte, J. C.Choe, S.Perán, M.Marchal, J. A.2016-08-082016-08-082015-11-13Jiménez G, López-Ruiz E, Kwiatkowski W, Montañez E, Arrebola F, Carrillo E, et al. Activin A/BMP2 chimera AB235 drives efficient redifferentiation of long term cultured autologous chondrocytes. Sci Rep. 2015; 5:16400http://hdl.handle.net/10668/2314Journal Article; Research Support, Non-U.S. Gov't;Autologous chondrocyte implantation (ACI) depends on the quality and quantity of implanted cells and is hindered by the fact that chondrocytes cultured for long periods of time undergo dedifferentiation. Here we have developed a reproducible and efficient chondrogenic protocol to redifferentiate chondrocytes isolated from osteoarthritis (OA) patients. We used morphological, histological and immunological analysis together with a RT-PCR detection of collagen I and collagen II gene expression to show that chondrocytes isolated from articular cartilage biopsies of patients and subjected to long-term culture undergo dedifferentiation and that these cells can be redifferentiated following treatment with the chimeric Activin A/BMP2 ligand AB235. Examination of AB235-treated cell pellets in both in vitro and in vivo experiments revealed that redifferentiated chondrocytes synthesized a cartilage-specific extracellular matrix (ECM), primarily consisting of vertically-orientated collagen fibres and cartilage-specific proteoglycans. AB235-treated cell pellets also integrated into the surrounding subcutaneous tissue following transplantation in mice as demonstrated by their dramatic increase in size while non-treated control pellets disintegrated upon transplantation. Thus, our findings describe an effective protocol for the promotion of redifferentiation of autologous chondrocytes obtained from OA patients and the formation of a cartilage-like ECM that can integrate into the surrounding tissue in vivo.enActivinasAnimalesBiopsiaCartílago articularCondrocitosColágenoMatriz extracelularHumanosOsteoartritisProteoglicanosReacción en cadena de la polimerasa de transcriptasa inversaTejido subcutáneoMedical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Gonadal Hormones::ActivinsMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Cytodiagnosis::BiopsyMedical Subject Headings::Anatomy::Musculoskeletal System::Cartilage::Hyaline Cartilage::Cartilage, ArticularMedical Subject Headings::Anatomy::Cells::Connective Tissue Cells::ChondrocytesMedical Subject Headings::Chemicals and Drugs::Macromolecular Substances::Polymers::Biopolymers::CollagenMedical Subject Headings::Anatomy::Cells::Cellular Structures::Extracellular Space::Extracellular MatrixMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Diseases::Musculoskeletal Diseases::Rheumatic Diseases::OsteoarthritisMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Chemicals and Drugs::Carbohydrates::Polysaccharides::ProteoglycansMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Nucleic Acid Amplification Techniques::Polymerase Chain Reaction::Reverse Transcriptase Polymerase Chain ReactionMedical Subject Headings::Anatomy::Tissues::Connective Tissue::Subcutaneous Tissueresearch article26563344open access10.1038/srep164002045-2322PMC4643338