ResearchIn-Press PreviewBone biology Open Access | 10.1172/jci.insight.181073
1Center for Regenerative Medicine and Skeletal Development, The University of Connecticut Health Center, Farmington, United States of America
2Institute for Systems Genomics, UConn, Storrs, United States of America
3Biomedical Engineering Department, The University of Connecticut Health Centre, Farmington, United States of America
4Department of Orthopaedic Surgery, The University of Michigan Medical School, Ann Arbor, United States of America
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1Center for Regenerative Medicine and Skeletal Development, The University of Connecticut Health Center, Farmington, United States of America
2Institute for Systems Genomics, UConn, Storrs, United States of America
3Biomedical Engineering Department, The University of Connecticut Health Centre, Farmington, United States of America
4Department of Orthopaedic Surgery, The University of Michigan Medical School, Ann Arbor, United States of America
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1Center for Regenerative Medicine and Skeletal Development, The University of Connecticut Health Center, Farmington, United States of America
2Institute for Systems Genomics, UConn, Storrs, United States of America
3Biomedical Engineering Department, The University of Connecticut Health Centre, Farmington, United States of America
4Department of Orthopaedic Surgery, The University of Michigan Medical School, Ann Arbor, United States of America
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1Center for Regenerative Medicine and Skeletal Development, The University of Connecticut Health Center, Farmington, United States of America
2Institute for Systems Genomics, UConn, Storrs, United States of America
3Biomedical Engineering Department, The University of Connecticut Health Centre, Farmington, United States of America
4Department of Orthopaedic Surgery, The University of Michigan Medical School, Ann Arbor, United States of America
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1Center for Regenerative Medicine and Skeletal Development, The University of Connecticut Health Center, Farmington, United States of America
2Institute for Systems Genomics, UConn, Storrs, United States of America
3Biomedical Engineering Department, The University of Connecticut Health Centre, Farmington, United States of America
4Department of Orthopaedic Surgery, The University of Michigan Medical School, Ann Arbor, United States of America
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1Center for Regenerative Medicine and Skeletal Development, The University of Connecticut Health Center, Farmington, United States of America
2Institute for Systems Genomics, UConn, Storrs, United States of America
3Biomedical Engineering Department, The University of Connecticut Health Centre, Farmington, United States of America
4Department of Orthopaedic Surgery, The University of Michigan Medical School, Ann Arbor, United States of America
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1Center for Regenerative Medicine and Skeletal Development, The University of Connecticut Health Center, Farmington, United States of America
2Institute for Systems Genomics, UConn, Storrs, United States of America
3Biomedical Engineering Department, The University of Connecticut Health Centre, Farmington, United States of America
4Department of Orthopaedic Surgery, The University of Michigan Medical School, Ann Arbor, United States of America
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Published May 23, 2024 - More info
We present a transcriptomic analysis that provides a better understanding of regulatory mechanisms within the healthy and injured periosteum. The focus of this work is on characterizing early events controlling bone healing during formation of periosteal callus on day 3 post fracture. Building upon our previous findings showing that induced Notch1 signaling in osteoprogenitors leads to better healing, we compared samples in which Notch 1 intracellular domain is overexpressed by periosteal stem/progenitor cells with control intact and fractured periosteum. Molecular mechanisms and changes in skeletal stem/progenitor cells (SSPCs) and other cell populations within the callus, including hematopoietic lineages were determined. Notably, Notch ligands were differentially expressed in endothelial and mesenchymal populations, with Dll4 restricted to endothelial cells, whereas Jag1 was expressed by mesenchymal populations. Targeted deletion of Dll4 in endothelial cells using Cdh5CreER resulted in negative effects on early fracture healing, while deletion in SSPCs using α-smooth muscle actin-CreER did not impact bone healing. Translating these observations into clinically relevant model of bone healing revealed the beneficial effects of delivering Notch ligands alongside osteogenic inducer, BMP2. These findings provide insights into the regulatory mechanisms within the healthy and injured periosteum, paving the way for novel translational approaches to bone healing.