In vivo two-photon imaging of vascular invasion and stem cell translocation in calvarial bone

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PROJECT SUMMARY Calvarial bone defects commonly occur as a result of trauma, congenital anomalies and iatrogenic conditions. The healing of bone defects relies on the regenerative capability of calvarial bones to replace damaged bone tissues and the availability of skeletal stem cells (SSCs) is one of the key factors for generating new bones to restore both structural and functional integrity. Calvarial SSCs that express marker gene Gli1, Axin2 or Prx1 reside in the sutural stem cell niche and contribute to calvarial bone homeostasis and healing after injury. It remains unclear how calvarial SSCs translocate from the sutural niche to distant regions of the calvarial bones for bone repair after injury of sites remote to the suture. Our preliminary analysis through 2-photon imaging indicates that Gli1-expressing calvarial SSCs not only reside in the sutural niche but also line the walls of blood vessels distributed widely throughout the postnatal calvarial bones. In this project, we will test the hypothesis that calvarial SSCs in the sutural niche could translocate with vascular invasion that initiates at the postnatal suture, and could reside within calvarial bones to contribute to bone regeneration after injury. We propose two specific aims for this project: 1) Determine if vascular invasion from the suture results in bone marrow cavity formation in postnatal calvarial bones, and 2) Determine if calvarial SSCs in the sutural niche translocate with vascular invasion to establish the SSC niche in bone marrow cavities of postnatal calvarial bones. This research proposal leverages the unique expertise of two investigative labs to address a key gap in our knowledge of calvarial healing. Successful completion of this exploratory research will set the stage for further mechanistic studies such as molecular regulation of calvarial SSC translocation, which could facilitate the development of new therapeutic approaches for rapid bone regeneration after injury.