Osteochondroreticular stem cell therapy for osteoarthritis: the right cells for the job

Abstract

Osteoarthritis (OA) is a disease of synovial joints characterized by clinical symptoms and pathology related to the whole joint including the periarticular tissues such as the muscles, ligaments and bone. Central to the pathogenesis and diagnosis, however, is the degeneration of articular cartilage. Current treatments include lifestyle modification to prevent further injury, analgesic drugs to help reduce symptoms and surgical interventions such as joint replacement. More recently stem cell therapies, either stimulating endogenous populations or infusing new cells, have been investigated. While OA is a multifactorial disorder, as a foundation to stem cell therapeutics one must accept the premise that OA pathogenesis, at least in part, is contributed to by stem cell dysfunction. Perhaps, a relative insufficiency of developmental articular chondrogenesis, inadequate replenishment during adult homeostasis or incomplete repair following mechanical and inflammatory challenges to cartilaginous integrity such as injury, obesity and ageing. Following the discovery of skeletal stem cells marked by the expression of Gremlin 1 (Grem1) being shown to give rise to chondrocytes in vivo, we studied transgenic mice to trace the Grem1-expressing cells in comparison to other MSC populations marked by the expression of Leptin receptor (LepR) and a common chondrocyte marker Aggrecan (Acan) in the knee articular cartilage. We found that Grem1-expressing cells label a stem cell population within the mouse knee articular cartilage in development as well as in adulthood. We then used a mouse model of OA, destabilisation of the medial meniscotibial (DMM) surgery, in these transgenic mice to test how injury modulates this population. We evaluated the single cell expression of these cells in the knee articular cartilage, by scRNASeq and generated a new mouse line to allow easy ablation of the Grem1 expressing cells within the knee articular cartilage. We also expanded these cells in vitro both to study their relative in vitro characteristics, as well as for injection back into our OA disease model. This thesis presents a comprehensive re-evaluation of articular stem cell biology and applies it to the important and increasingly global clinical problem of osteoarthritis. This work has made new discoveries, generated new transgenic mouse reagents and has stimulated ongoing translational research to better understand osteoarthritis and develop new approaches to its prevention and treatment.