15502-m-pleumeekers

INTRODUCTION Cartilage has a very limited capacity for self-regeneration. Untreated lesions - caused by trauma, tumors, congenital malformation or age related degeneration - persist indefinitely and ultimately require surgical intervention. However, current treatments are unsuccessful for long-term repair; resulting in a need for novel repair strategies. Cell-based cartilage repair holds promise for restoring missing or destroyed cartilage and has the potential to overcome limitations of current treatments, while re-establishing the unique biological and functional properties of the tissue. One of the major challenges herein is defining an appropriate cell source. Current cell- based surgical treatments for cartilage lesions are predominantly based on the use of either (1) chondrocytes or (2) mesenchymal stem cells (MSCs). These cell-based procedures are however associated with specific disadvantages. Chondrocytes from several anatomical locations (e.g. joint, rib, nose, ear, meniscus) have been investigated for their application in cartilage regeneration. [39-59] However, to generate a construct of reasonable size, large numbers of chondrocytes are required, necessitating the use of culture-expansion. In monolayer culture-expansion, chondrocytes dedifferentiate; they change phenotypically to a fibroblast-like morphology and lose their chondrogenic gene-expression capacity. Chondrocyte-dedifferentiation usually results in fibrous and mechanically inferior cartilage, making them less suitable for cell-based cartilage repair. [61] In contrast, multipotent cells, like MSCs, achieved considerable attention as alternative cells, as they can undergo multiple population doublings without losing their chondrogenic potential and have the capacity to differentiate into cartilage tissue under appropriate culture conditions. [64-68] Furthermore, MSCs are easily available from several tissues, including bone marrow and adipose tissue, which makes culture-expansion unnecessary. However, the single use of MSCs for cell-based cartilage repair is currently debated, since the cartilage tissue formed is unstable and predisposed to mineralization and ossification in vivo . [69-71, 240, 241] Currently, combining both cell sources holds great promise for cell-based cartilage repair as it reduces the required number of chondrocytes and diminishes many disadvantages of both individual cell types. Moreover, by decreasing the amount of chondrocytes required (≤ 20% of the total cell mixture), culture-expansion is no longer necessary, which would allow the use of freshly isolated primary chondrocytes leading to improved cartilage formation. [76] Unfortunately, in depth understanding of the cellular interaction pathways betweenMSCs and chondrocytes is under debate in literature: It is thought that the co-culture effect is either credited by (1) chondrocyte driven MSC-differentiation or ascribed to (2) chondrocytes, whose cartilage-forming capacity and proliferation activity are enhanced in the presence of MSCs. [81] In recent years, the trophic and paracrine functions of MSCs appeared most critical in this process, rather than the simple chondrogenic differentiation of MSCs alone. However, little is known as to whether their trophic function is a general characteristic of MSCs or dependent on the origin of the MSC source. MSCs from several anatomical locations have been applied in co-culture. Independent on their origin, mixed cell cultures of chondrocytes and MSCs have been demonstrated to generally improve chondrogenesis as well as to reduce hypertrophy and tissue mineralization. [75, 81, 242] In contrast, three co-culture studies using adipose- 85 AMSCs OR BMSCs FULFILL A TROPHIC ROLE IN CO-CULTURE 5