Fig. 9. A Wnt-mediated conversion of stromal cell identity orchestrates skeletal regeneration.

a Quiescent CXCL12⁺ bone marrow stromal cells (BMSCs) in perisinusoidal space are marked by Cxcl12-creER upon tamoxifen injection. These cells are preferentially localized in a non-endosteal location of the marrow space, associated with a reticular morphology, abundant cytokine expression and little colony-forming activities. These cells do not become cortical bone osteoblasts in homeostasis, but can be readily converted to marrow adipocytes. b A proposed diagram of the bone marrow stromal cell lineage. In homeostasis, CXCL12^high reticular cells and COL1A1^high osteoblasts represent two opposite differentiated states of the bone marrow stromal cell lineage. The transition between these two cell types is continuous, wherein intermediate-state cells represent a precursor cell population. c Wnt-mediated cellular plasticity of CXCL12⁺ reticular cells during injury responses. In homeostasis, Cxcl12-creER⁺ reticular cells are in a Wnt-inhibitory state by expressing potent Wnt inhibitors, such as Sfrp1, Sfrp2, and Sfrp4. During injury responses, Cxcl12-creER ⁺ reticular cells are brought into a reticular-osteoblast hybrid state by injury-induced cues, associated with upregulation of osteoblast-signatures and a critical canonical Wnt component, β-catenin. Subsequently, Wnt/β-catenin signaling induces cell identity conversion of Cxcl12-creER⁺ reticular cells into pre-osteoblasts, which are featured by a skeletal stem cell-like state with partial commitment to the osteoblast lineage. These cells can be recruited to cortical bone defect and functionally contribute to skeletal regeneration.