Xenotransplantation of pig chondrocytes: therapeutic potential and barriers for cartilage repair

Abstract

Transplantation may be the best option for the repair of many cartilage lesions including early osteoarthritis. Currently, autologous and allogeneic chondrocytes are grafted into cartilage defects to treat selected patients with moderate clinical success. However, their limited use justifies exploring novel therapies for cartilage repair. Xenotransplantation could become a solution by offering high cell availability, quality and genetic engineering capabilities. The rejection process of xenogeneic cartilage is thus being elucidated in order to develop counteractive strategies. Initial studies determined that pig cartilage xenografts are rejected by a slow process comprising humoral and cellular responses in which the galactose α1,3-galactose antigen participates. Since then, our group has identified key mechanisms of the human response to pig chondrocytes (PCs). In particular, human antibody and complement contribute to PC rejection by inducing a pro-inflammatory milieu. Furthermore, PCs express and up-regulate molecules which are functionally relevant for a variety of cellular immune responses (SLA-I, the potent co-stimulatory molecule CD86, and adhesion molecules VCAM-1 and ICAM-1). These participate by triggering a T cell response, as well as supporting a prominent role of the innate immune responses led by natural killer (NK) cells and monocytes/macrophages. Human NK cells lyse PCs by using selected NK activating receptors, whereas human monocytes are activated by PCs to secrete cytokines and chemokines. All this knowledge sets the bases for the development of genetic engineering approaches designed to avert rejection of xenogeneic chondrocytes and leads the way to developing new clinical applications for cartilage repair.

Biodistribution and Immunogenicity of Allogeneic Mesenchymal Stem Cells in a Rat Model of Intraarticular Chondrocyte Xenotransplantation

“…The use of xenogeneic cells could greatly benefit the development of this treatment modality as they could be obtained in sufficient quantity following protocols with high quality and control ( 1 ). Notably, these cells could be genetically engineered to match the needs of every particular application in clinical practice ( 2 , 3 ). Xenogeneic porcine chondrocytes are differentiated cells with the capacity to form hyaline cartilage in in vitro and in vivo models ( 4 , 5 ).…”

Coculturing of mesenchymal stem cells of different sources improved regenerative capability of osteochondral defect in the mature rabbit: An in vivo study

“…30 Several studies have used allogeneic chondrocytes and MSCs for articular cartilage and meniscal repair, 31 –33 and xenogeneic chondrocytes in the case of chondral and osteochondral defects, without evidence of immune response. 34 Trials of chondrocytes cocultured with MSCs have been using up to 75% chondrocytes, achieving equal or greater chondrogenic potential compared with the sue of 100% chondrocytes. 35 Hence, further studies will be necessary to evaluate the best SMSCs/BMSCs ratio in the coculture system either for in vitro and in vivo assessment of osteochondrogenic potential with long-term evaluations.…”

Development and Characterization of Acellular Caprine Choncal Cartilage Matrix for Tissue Engineering Applications

“…There have been numerous instances of using variety of xenografts in cartilage tissue engineering. 42-44 Also, acellular cartilages are being parallelly employed 9,43,45 but mostly limited to in vitro analysis. Despite the importance of in vitro experiments, results of in vivo analysis play an influential role for any successful clinical applications as there is a noticeable difference between the two environments.…”