Traditional models of musculoskeletal regeneration proposed that tissue repair is mediated by mesenchymal stromal and progenitor populations (MSCs). However, these populations are highly heterogeneous, often exhibit limited or inconsistent in vivo self-renewal, and display marked variation in differentiation potential depending on their tissue of origin. As a result, MSC-based models have struggled to explain the distinct regenerative capacities, cellular hierarchies, and disease susceptibilities observed across different musculoskeletal tissues.

Recent work has instead revealed the existence of tissue-specific stem cell populations that govern the maintenance and repair of individual skeletal tissues, including bone, cartilage, tendons and ligaments. These skeletal stem cells (SSCs) have clearly defined lineage hierarchies and are validated by rigorous functional assays that demonstrate self-renewal and multipotency in vivo.

Here, we will discuss the recent identification of the tendon/ligament stem cell that drives tendon regeneration, as well as novel candidate cartilage stem cells that support cartilage homeostasis and repair. While these cells share common molecular markers and regulatory pathways that control stem cell function and lineage progression, they display distinct differentiation capacities reflecting the specialized biology of their resident tissues.

Together, these findings support a model in which tissue-specific stem cells underlie the physiology and pathological responses of tendon and cartilage, providing a cellular framework for understanding degeneration, impaired healing, and regenerative medicine approaches across the musculoskeletal system.