Activation of Skeletal Stem and Progenitor Cells for Bone Regeneration Is Driven by PDGFRβ Signaling

Abstract

Bone repair and regeneration critically depend on the activation and recruitment of osteogenesis-competent skeletal stem and progenitor cells (SSPCs). Yet, the origin and triggering cues for SSPC propagation and migration remain largely elusive. Through bulk and single-cell transcriptome profiling of fetal osterix (Osx)-expressing cells, followed by lineage mapping, cell tracing, and conditional mouse mutagenesis, we here identified PDGF-PDGFRβ signaling as critical functional mediator of SSPC expansion, migration, and angiotropism during bone repair. Our data show that cells marked by a history of Osx expression, including those arising in fetal or early postnatal periods, represent or include SSPCs capable of delivering all the necessary differentiated progeny to repair acute skeletal injuries later in life, provided that they express functional PDGFRβ. Mechanistically, MMP-9 and VCAM-1 appear to be involved downstream of PDGF-PDGFRβ. Our results reveal considerable cellular dynamism in the skeletal system and show that activation and recruitment of SSPCs for bone repair require functional PDGFRβ signaling.

Keywords: PDGF; PDGF receptor; blood vessels; bone; bone marrow stromal cells; bone regeneration; fracture repair; osteoprogenitors; pericytes; skeletal stem cells.