Identification of Functionally Distinct Mx1+αSMA+ Periosteal Skeletal Stem Cells

• Published in: Cell stem cell 2019-12, Vol.25 (6), p.784-796.e5
• Main Authors: Ortinau, Laura C., Wang, Hamilton, Lei, Kevin, Deveza, Lorenzo, Jeong, Youngjae, Hara, Yannis, Grafe, Ingo, Rosenfeld, Scott B., Lee, Dongjun, Lee, Brendan, Scadden, David T., Park, Dongsu
• Format: Article
• Language: English
• Subjects: Actins - genetics; Actins - metabolism; Adolescent; Adult; Animals; bone repair; CCL5; Cell Movement - physiology; Child; Female; Flow Cytometry; Fluorescent Antibody Technique; Humans; Immunohistochemistry; in vivo real-time imaging; Male; Mice, Inbred C57BL; Microarray Analysis; Myxovirus Resistance Proteins - genetics; Myxovirus Resistance Proteins - metabolism; periosteum; Periosteum - cytology; Periosteum - metabolism; Reverse Transcriptase Polymerase Chain Reaction; skeletal stem cells; stem cell migration; Stem Cells - cytology; Stem Cells - metabolism; Young Adult
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2019.11.003

The periosteum is critical for bone maintenance and healing. However, the in vivo identity and specific regulatory mechanisms of adult periosteum-resident skeletal stem cells are unknown. Here, we report animal models that selectively and durably label postnatal Mx1+αSMA+ periosteal stem cells (P-SSCs) and establish that P-SSCs are a long-term repopulating, functionally distinct SSC subset responsible for lifelong generation of periosteal osteoblasts. P-SSCs rapidly migrate toward an injury site, supply osteoblasts and chondrocytes, and recover new periosteum. Notably, P-SSCs specifically express CCL5 receptors, CCR3 and CCR5. Real-time intravital imaging revealed that the treatment with CCL5 induces P-SSC migration in vivo and bone healing, while CCL5/CCR5 deletion, CCR5 inhibition, or local P-SSC ablation reduces osteoblast number and delays bone healing. Human periosteal cells express CCR5 and undergo CCL5-mediated migration. Thus, the adult periosteum maintains genetically distinct SSC subsets with a CCL5-dependent migratory mechanism required for bone maintenance and injury repair. [Display omitted] •Mx1 and αSMA combination selectively labels SSCs resident in adult periosteum (P-SSC)•Mx1+αSMA+ P-SSCs are long-term repopulating and functionally distinct SSCs•Mx1+αSMA+ P-SSCs and human P-SSCs specifically express the CCL5 receptor CCR5•CCL5 induces P-SSC migration in vivo, and its loss delays bone healing Ortinau et. al identified long-term repopulating, functionally distinct adult periosteal skeletal stem cells (P-SSCs) that can be marked by a combination of Mx1 and αSMA. These P-SSCs are critical for periosteal bone maintenance, specifically express CCL5 receptors, CCR5, and have a unique CCL5-dependent migratory mechanism required for injury repair.