Harnessing the diversity and potential of endogenous skeletal stem cells for musculoskeletal tissue regeneration

Abstract In our aging society, the degeneration of the musculoskeletal system and adjacent tissues is a growing orthopedic concern. As bones age, they become more fragile, increasing the risk of fractures and injuries. Furthermore, tissues like cartilage accumulate damage, leading to widespread joint issues. Compounding this, the regenerative capacity of these tissues declines with age, exacerbating the consequences of fractures and cartilage deterioration. With rising demand for fracture and cartilage repair, bone-derived stem cells have attracted significant research interest. However, the therapeutic use of stem cells has produced inconsistent results, largely due to ongoing debates and uncertainties regarding the precise identity of the stem cells responsible for musculoskeletal growth, maintenance and repair. This review focuses on the potential to leverage endogenous skeletal stem cells (SSCs)—a well-defined population of stem cells with specific markers, reliable isolation techniques, and functional properties—in bone repair and cartilage regeneration. Understanding SSC behavior in response to injury, including their activation to a functional state, could provide insights into improving treatment outcomes. Techniques like microfracture surgery, which aim to stimulate SSC activity for cartilage repair, are of particular interest. Here, we explore the latest advances in how such interventions may modulate SSC function to enhance bone healing and cartilage regeneration.