Stem Cell Applications, Articular Cartilage

Background

Type II collagen is by far the most dominant fibrous component in articular cartilage, but it also consists of other crosslinked types of collagen (VI, IX, X, and XI). The matrix includes proteo—glycans (including aggrecan), which are extremely hydrophilic. Together, collagen and proteoglycans make up approximately 30 percent of the tissue. The other 70 percent is essentially water, held in place by electrochemical interactions with the proteoglycans. The hydrophilic nature of normal cartilage provides a hydrostatic cushion to help bear and distribute compressive loads, a characteristic that is lost with OA. Chondrocytes comprise 95 percent of the total cells and are the primary resource for self—renewal of the cartilage matrix. Chondrocytes are limited in number and slow to replicate, even on tissue injury. When expanded, they often lose their phenotype. Therefore, clinicians and scientists are investigating other ways to support and enhance chondrocyte production in damaged or arthritic articular cartilage. One current surgical treatment for localized lesions harvests autologous chondrocytes from an uninjured but low—functional demand site, expands them in culture, places them onto a scaffold, and implants the cell layer onto the defect site with a perios—teal graft covering. Limitations of this Carticel technique include limited durability, limited tissue availability, and donor site morbidity. Other clinical treatment methods include joint replacement or fusion, allogeneic implants, mosaicplasty with autogenic osteochondral grafts, wedge osteotomy to reduce contact pressure, chondral surfacing, or [Page 517]microfracture of the subchondral bone to induce a more robust healing response. All methods have drawbacks, including their invasiveness, possible infection or rejection, limited longevity, and scarring. Stem cells provide an optimistic alternative for healing or regenerating this complex tissue, which is otherwise limited by physiology, biocom—patibility, and tissue sources.

Cell Type

Stem cells are ideal for regenerating or repairing damaged cartilage, as long as they can maintain a sufficient cell mass in the defect to differentiate into a chondrocytic phenotype that will produce critical components of the extracellular matrix (ECM). Embryonic stem cells (ESCs) offer promise for cartilage engineering in that they are pluripo—tent and differentiate into many different somatic cell types. Mouse ESCs cultured as embryoid bodies in the presence of bone morphogenic protein (BMPs) 2 and 4 have proven positive for chon—drocyte differentiation with Alcian blue staining. Likewise, when pellet cultures of embryoid bodies are exposed to transforming growth factor (TGF) B3, there is an increase in collagen content and GAG (glycosaminoglycan) production after 14 days and an increased expression of cartilage—specific extracellular matrix genes.

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