Multifunctional LepR⁺ skeletal stem/progenitor cells for bone and marrow homeostasis.

Bone is a multifunctional organ that provides structural support and hosts the bone marrow, a key site for hematopoiesis and systemic homeostasis. These dual features have long attracted the attention of both bone biologists and hematologists. Each field has pursued the identification of stem-like cells responsible for hard tissue formation and the regulatory microenvironment/niche that supports hematopoietic stem cells (HSCs), which give rise to all blood cell lineages. Converging advances in bone and hematopoietic biology have led to the identification of skeletal stem/progenitor cells (SSPCs), a multifunctional population that gives rise to osteolineage cells and serves as a principal component of the HSC niche. This landmark discovery was largely enabled by Cre/loxP-based genetic mouse models. Among them, the leptin receptor (LepR)-Cre system has become one of the most widely used tools in skeletal stem cell research worldwide. In this review, we summarize the historical background and recent advances in SSPC research, specifically LepR+ SSPCs, highlighting their function and lineage plasticity during development, adolescence, aging, and fracture healing. Advanced genetic labeling-based studies and single-cell transcriptomics unveiled the fate, dynamics and indispensible roles of LepR⁺ SSPCs under both homeostatic and pathological conditions.