Discovery of a periosteal stem cell mediating intramembranous bone formation

Bone is comprised of separate inner endosteal and outer periosteal compartments, each with distinct contributions to bone physiology and each maintaining separate pools of cells due to physical separation by the bone cortex. While the skeletal stem cell giving rise to endosteal osteoblasts has been extensively studied, the identification of a periosteal stem cell has been elusive(1–5). Here, we identify a periosteal stem cell (PSC) present in the long bones and calvarium of mice that displays clonal multipotency, self-renewal and sits at the apex of a differentiation hierarchy. Single cell and bulk transcriptional profiling show that PSCs display distinct transcriptional signatures in comparison with both other skeletal stem cells and mature mesenchymal cells. While other skeletal stem cells form bone via an initial cartilage template using the endochondral pathway(4), PSCs form bone via a direct intramembranous route, providing a cellular basis for the divergence between intramembranous versus endochondral developmental pathways. However there is plasticity in this division, as PSCs acquire endochondral bone formation capacity in response to injury. Genetic blockade of the ability of PSCs to give rise to bone-forming osteoblasts results in selective impairments in cortical bone architecture and defects in fracture healing. A cell analogous to PSCs is present in the human periosteum, raising the possibility that PSCs are attractive targets for drug and cellular therapy for skeletal disorders. Moreover, the identification of PSCs provides evidence that bone contains multiple pools of stem cells, each with distinct physiologic functions.