15502-m-pleumeekers

percent of the chondrocytes can easily be replaced by MSCs without influencing cartilage matrix production. Co-culture supports the use of primary chondrocytes without the interference of culture-expansion and the process of redifferentiation, and only requires a small tissue biopsy of undamaged cartilage. Moreover, the use of cartilage remnants can be considered, such as chondrocytes derived from microtic cartilage. [79, 369, 370] (2) Stem cells Pluripotent stem cells, like human embryonic stem cells (ESCs) [371] or induced pluripotent stem cells (iPSCs) [372], are highly potential cell sources for tissue engineering purposes. These cells have unlimited capacity for self-renewal and the ability to differentiate into any mature cell type. In combination with chondrocytes, pluripotent stem cells improve cartilage formation in vitro and in vivo . [373-376] However, the use of human ESCs and iPSCs is currently impeded by the risk of teratoma formation and oncogenicity. [377, 378] Moreover, the application of human ESCs raise ethical concerns regarding their isolation from human embryos. To date, pluripotent stem cells seems mainly valuable for research purposes and not yet for clinical application. Stem cells that have been most extensively studied for their application in chondrogenic co-cultures are MSCs. Unlike pluripotent stem cells, MSCs are multipotent possessing committed lineage differentiation potential and lacking unlimited self-renewal capacity. They are however (1) easily available from several tissues, including bone marrow, adipose tissue, synovium, peripheral blood, dental pulp, placenta, umbilical cord, and skeletal muscle [63], (2) have the ability to reconstitute cartilage tissue by the ability to chondrogenically differentiate [80, 253-262], and (3) possess chondro-inductive capacity that enables chondrocytes to facilitate cartilage repair and regeneration [379]. To date, MSCs from adipose tissue (AMSCs) and bone marrow (BMSCs) are best characterized. Our results from chapter five and six support a general trophic or immunomodulatory role for human AMSCs and BMSCs on chondrocytes in co-culture, in accordance to Wu [246] and Maumus et al. [247]. Although both cell sources share comparable immunomodulatory modalities and their immunophenotypes and gene-expression profiles are greater than 90% identical [380], they do not necessarily behave the same. Differences on molecular level have been recognized by others, reviewed by Strioga et al . [380] For instance, gene-expression profiles of BMSCs were only involved in WNT-signaling and differentiation pathways, whereas genes expressed uniquely by AMSCs were responsible for cellular communication and transcription control. [232] In addition, 18% of the generated proteins were found to be differentially produced between AMSCs and BSMCs [232]: compared to BMSCs, AMSCs secrete significantly more VEGF-D [269], IGF-1 [269, 270], IL-8 [269] and IL-6 [269, 271], and significantly less SDF-1 [272] and TFGβ1 [272]. Finally, dissimilarities were also observed between AMSCs and BMSCs in monoculture in chapter four . These location-specific MSCs possessed distinctive proliferation capacities and a dissimilar potential to chondrogenically differentiate. However, whether the differences between AMSCs and BMSCs are fully explained by the uniqueness of the stem cell population, or are just inherent to their heterogeneity and related to isolation and culture protocols, remains unclear. Most importantly, despite the minor differences between these 181 DISCUSSION AND FUTURE PERSPECTIVES 9