Immature myeloid cells are critical for enhancing bone fracture healing through angiogenic cascade.
Bone fractures heal with overlapping phases of inflammation, cell proliferation, and bone remodeling. Osteogenesis and angiogenesis work in concert to control many stages of this process, and when one is impaired it leads to failure of bone healing, termed a nonunion. During fracture repair, there is an infiltration of immune cells at the fracture site that not only mediate the inflammatory responses, but we hypothesize they also exert influence on neovasculature. Thus, further understanding the effects of immune cell participation throughout fracture healing will reveal additional knowledge as to why some fractures heal while others form nonunions, and lead to development of novel therapeutics modulating immune cells, to increase fracture healing and prevent nonunions. Using novel femoral segmental and critical-size defect models in mice, we identified a systemic and significant increase in immature myeloid cell (IMC) infiltration during the initial phase of fracture healing until boney union is complete. Using gemcitabine to specifically ablate the IMC population, we confirmed delayed bone healing. Further, adoptive transfer of IMC increased bone growth in a nonunion model, signifying the role of this unique cell population in fracture healing. We also identified IMC post-fracture have the ability to increase endothelial cell migration, and tube formation, signaling the essential communication between the immune system and angiogenesis as a requirement for proper bone healing. Based on this data we propose that IMC may play a significant role in fracture healing and therapeutic targeting of IMC after fracture would minimize the chances of eventual nonunion pathology.
Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, United States.
Seth
S
Levy
Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, United States.
Joseph M
JM
Feduska
Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, United States.
Anandi
A
Sawant
Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, United States.
Shawn R
SR
Gilbert
Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, United States.
Jonathan A
JA
Hensel
Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, United States. Electronic address: pons@uab.edu.
Selvarangan
S
Ponnazhagan
D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002469:Cell Separation; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D017102:Fracture Healing / Q000187:drug effects; D050723:Fractures, Bone / Q000473:pathology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007165:Immunosuppression Therapy; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology* / Q000187:drug effects; D000072737:Myeloid-Derived Suppressor Cells / Q000166:cytology / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D010012:Osteogenesis / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000093542:Gemcitabine
D003841:Deoxycytidine; D000093542:Gemcitabine
Angiogenesis; Bone fracture; Bone marrow; Myeloid cell; Wound healing
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