The clinical problems relating to the skeleton (bone, cartilage and bone marrow stromal niche) could be ultimately addressed by a thorough understanding of how the skeleton develops and is maintained from a stem cell point of view. By identifying and characterizing the human skeletal stem cell (hSSC) and its downstream progenitors, novel cell-based therapies can be developed for treating conditions affecting the bone marrow stromal niche. We seek to define the cellular origins of skeletal tissues to study how the human skeleton is formed and maintained throughout life. We want to understand how bone and cartilage tissue are generated and organized into skeletal structures at the cellular level, and how skeletal progenitors respond to regenerative demands in response to injury and stress. We also hope to understand the underlying molecular mechanisms involved in these processes, and how they are genetically programmed. Our experimental strategy is designed to address these questions by identifying and analyzing the distinct progenitors of skeletal tissue, beginning with the human skeletal stem cell (hSSC), and its progression through intermediate multipotent progenitor phases into the committed progenitors of mature osteoblasts, chondrocytes and stroma. We will accompany functional assays with transcriptome analyses to identify defining genetic changes occurring at each progenitor stage. We have identified several distinct populations of skeletal progenitor cells from human fetal bones including a unipotent cartilage progenitor population, a bone and stroma forming population, and what we believe to be the human bone, cartilage and stromal niche progenitor (BCSP).