High-resolution imaging of the osteogenic and angiogenic interface at the site of murine cranial bone defect repair via multiphoton microscopy
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eLife assessment
The authors present very exciting findings on the cranial bone defect repair using cutting-edge multiphoton imaging to study the role of different vessel subtypes and related oxygen and metabolic microenvironments. The study used microscopy to visualize the oxygen distribution and energy metabolism within the defects at different time points during the process of bone healing. This allows one to understand the pathophysiological progressions of bone diseases and regeneration. It will also provide critical information to optimize the therapeutic bone healing and regeneration approach for different clinical situations.
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Abstract
The spatiotemporal blood vessel formation and specification at the osteogenic and angiogenic interface of murine cranial bone defect repair were examined utilizing a high-resolution multiphoton-based imaging platform in conjunction with advanced optical techniques that allow interrogation of the oxygen microenvironment and cellular energy metabolism in living animals. Our study demonstrates the dynamic changes of vessel types, that is, arterial, venous, and capillary vessel networks at the superior and dura periosteum of cranial bone defect, suggesting a differential coupling of the vessel type with osteoblast expansion and bone tissue deposition/remodeling during repair. Employing transgenic reporter mouse models that label distinct types of vessels at the site of repair, we further show that oxygen distributions in capillary vessels at the healing site are heterogeneous as well as time- and location-dependent. The endothelial cells coupling to osteoblasts prefer glycolysis and are less sensitive to microenvironmental oxygen changes than osteoblasts. In comparison, osteoblasts utilize relatively more OxPhos and potentially consume more oxygen at the site of repair. Taken together, our study highlights the dynamics and functional significance of blood vessel types at the site of defect repair, opening up opportunities for further delineating the oxygen and metabolic microenvironment at the interface of bone tissue regeneration.
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eLife assessment
The authors present very exciting findings on the cranial bone defect repair using cutting-edge multiphoton imaging to study the role of different vessel subtypes and related oxygen and metabolic microenvironments. The study used microscopy to visualize the oxygen distribution and energy metabolism within the defects at different time points during the process of bone healing. This allows one to understand the pathophysiological progressions of bone diseases and regeneration. It will also provide critical information to optimize the therapeutic bone healing and regeneration approach for different clinical situations.
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Reviewer #1 (Public Review):
It is a very interesting study that provides a clear and sophisticated description of the dynamic changes that take place at a calvaria defect site in terms of blood vessels, osteoblastic cells, and gradient of O2. It uses cutting-edge techniques. It is likely to become a critical reference for the scientific community.
It is a descriptive paper, but the data are solid.
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Reviewer #2 (Public Review):
This study was built on the authors' previous publications to visualize angiogenesis and osteogenesis processes at subcritical-sized mouse calvarial defects using multiphoton microscopy. This provides, for the first time, the visible imaging of bone healing and vascularization within the defect after different time points of injury, although the physiological progression of calvarial bone healing was already known. More interestingly, the study used microscopy to visualize the oxygen distribution and energy metabolism within the defects at different time points during the process of bone healing. This allows one to understand the pathophysiological progressions of bone diseases and regeneration. It will also provide critical information to optimize the therapeutic bone healing and regeneration approach for …
Reviewer #2 (Public Review):
This study was built on the authors' previous publications to visualize angiogenesis and osteogenesis processes at subcritical-sized mouse calvarial defects using multiphoton microscopy. This provides, for the first time, the visible imaging of bone healing and vascularization within the defect after different time points of injury, although the physiological progression of calvarial bone healing was already known. More interestingly, the study used microscopy to visualize the oxygen distribution and energy metabolism within the defects at different time points during the process of bone healing. This allows one to understand the pathophysiological progressions of bone diseases and regeneration. It will also provide critical information to optimize the therapeutic bone healing and regeneration approach for different clinical situations.
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Reviewer #3 (Public Review):
In this manuscript, authors present very exciting findings on the cranial bone defect repair using cutting-edge multiphoton imaging to study the role of different vessel subtypes and related oxygen and metabolic microenvironments. The authors used transgenic reporter mouse models to label and track blood vessel subtypes at the site of repair. They demonstrate the role of capillary subtypes at the repair sites in skull bone and provide evidence for the existence of specialized metabolic environments for coupling angiogenesis and osteogenesis. The study provides important insights into the dynamics and role of blood vessel subtypes in cranial bone defect repair.
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