Abstract
Articular cartilage functions as a shock absorber and facilitates the free movement of joints. Currently, there are no therapeutic drugs that promote the healing of damaged articular cartilage. Limitations associated with the two clinically relevant cell populations, human articular chondrocytes and mesenchymal stem cells, necessitate finding an alternative cell source for cartilage repair. Human embryonic stem cells (hESCs) provide a readily accessible population of self-renewing, pluripotent cells with perceived immunoprivileged properties for cartilage generation. We have developed a robust method to generate 3D, scaffold-free, hyaline cartilage tissue constructs from hESCs that are composed of numerous chondrocytes in lacunae, embedded in an extracellular matrix containing Type II collagen, sulphated glycosaminoglycans and Aggrecan. The elastic (Young’s) modulus of the hESC-derived cartilage tissue constructs (0.91 ± 0.08 MPa) was comparable to full-thickness human articular cartilage (0.87 ± 0.09 MPa). Moreover, we have successfully scaled up the size of the scaffold-free, 3D hESC-derived cartilage tissue constructs to between 4.5 mm and 6 mm, thus enhancing their suitability for clinical application.
Highlights
Articular cartilage functions as a shock absorber and facilitates the free movement of joints
The Human embryonic stem cells (hESCs)-derived chondrocytes displayed a dramatic reduction in the expression of the pluripotency proteins, OCT4 (p < 0.001), SOX2 (p < 0.01) and NANOG (p < 0.001), and a gain in the expression of chondrogenic markers, SOX9 (p < 0.001) and Type II collagen (p < 0.05), compared to hESCs (Fig. 1A,B)
Robust expression of the chondrogenic transcription factor SOX9 was observed in the hESC-derived chondrocytes, together with abundant deposition of Type II collagen in the extracellular matrix (Fig. 1C)
Summary
Articular cartilage functions as a shock absorber and facilitates the free movement of joints. Limitations associated with the two clinically relevant cell populations, human articular chondrocytes and mesenchymal stem cells, necessitate finding an alternative cell source for cartilage repair. Human embryonic stem cells (hESCs) provide a readily accessible population of self-renewing, pluripotent cells with perceived immunoprivileged properties for cartilage generation. We have developed a robust method to generate 3D, scaffold-free, hyaline cartilage tissue constructs from hESCs that are composed of numerous chondrocytes in lacunae, embedded in an extracellular matrix containing Type II collagen, sulphated glycosaminoglycans and Aggrecan. Regenerative medicine approaches for articular cartilage repair have focused on the generation of cartilage tissue primarily from clinically relevant cell populations, namely human articular chondrocytes (HACs), chondroprogenitor cells (CPCs) and bone marrow-derived mesenchymal stem cells (MSCs). Which, in turn, cause donor site morbidity; a limited number of chondrocytes can be isolated from the cartilage biopsies, requiring expensive cell culture for expansion of chondrocyte numbers in vitro; dedifferentiation of chondrocytes due to 2D monolayer culture and their limited lifespan in vitro[2]
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