Cartilage Tissue Engineering; the search for chondrogenic progenitor cells and associated signalling pathways
Year: 2009
Type: dissertation
Abstract: The socioeconomic cost of articular cartilage related diseases in the Western world is very\nhigh. The suffering of the individual patient is even more problematic. Different methods are\nused today to treat this large, heterogeneous group of patients, one of which has been in use\nfor more than 20 years: cell based autologous chondrocyte implantation (ACI). Irrespective of\ntreatment method, a great deal remains to be done to improve our knowledge of what occurs\nat molecular and cellular levels. The overall aim of this thesis was therefore to find\nchondrocytes with stem cell properties in cartilage used for ACI, and to study the associated\nmolecular signalling pathways.\nThe helix-loop-helix (HLH) transcription factor Id1 was demonstrated to play a role in\nregulating proliferation of cultured human articular chondrocytes, indicating a role for the\nfamily of HLH proteins in chondrocytes. Human articular chondrocytes cultured in agarose\nsuspension demonstrated subpopulations with different growth potential. Some showed\nmesenchymal stem cell (MSC) properties. To be able to locate potential stem cells in vivo, a\nrabbit BrdU model, identifying slow cycling cells was used. Stem cells were not only\nidentified in the articular cartilage but also in the groove of Ranvier located in the periphery\nof the epiphyseal growth plate. The groove of Ranvier also exhibited properties as a stem cell\nniche structure. Further biopsies from human normal articular cartilage, as well as regenerated\nand repaired cartilage after ACI were studied. The human normal articular cartilage\ndemonstrated expression of the stem cell associated markers STRO-1 and Bcrp1 in cells in the\nsuperficial zone, and activity of the fundamental Wnt (Wingless-related proteins) and Notch\nsignalling pathways. The distribution showed a distinct zonal pattern in the normal cartilage.\nIn biopsies from regenerated cartilage with almost normal histological architecture, the\nmarkers and pathways studied demonstrated a distinct zonal pattern similar to that in normal\ncartilage. Biopsies taken from repaired cartilage with more or less fibrocartilage formation\nand with a disorganized matrix, showed increased Stro-1 expression and activity for the Wnt\npathway throughout the biopsies. The supposed stem cell marker Bcrp1 was expressed in a\nsparse population of cells independently of cartilage tissue studied.\nThis thesis demonstrates that in cartilage there are subpopulations of cells with mesenchymal\nstem cell properties, and that it is possible to identify and select these populations for further\nstudy of their properties as stem cells and their usefulness for transplantation. The HLH, Wntand\nNotch signalling pathways are closely involved in articular cartilage repair and\nregeneration. The stem cells and signalling pathways may represent potential drug targets or valuable tools in the tissue engineering of joint tissue.
Author: Maria Thornemo
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1575758750