Transient activation of notch signaling enhances endogenous stromal cell expansion and subsequent bone defect repair

BACKGROUND: Following traumatic bone loss or removal of bone tumors, the failure of bone allograft transplantation for large bone defect repair remains a significant problem in orthopedics. Therefore, new strategies that can efficiently enhance allograft healing and long-term incorporation are critically needed. METHOD: In this study, we first injected Notch-activating Jagged1 peptide to mice and then isolated bone marrow tissues and cells for proliferation and differentiation assays. Femur bone allograft surgery was also performed in Jagged1 pre-treated mice, and bone defect healing process were monitored by histology, Micro-CT and biomechanical testing. RESULT: Our results showed that Jagged1 therapeutic injection is sufficient to maximally activate Notch and promote bone marrow stromal cell proliferation in vivo, while no effects on bone structure were observed. More importantly, Jagged1 pre-treatment significantly promoted bone callus formation and increased bone mechanical strength during allograft healing in a femur bone defect mouse model. CONCLUSION: This study reveals that Notch in vivo activation can be induced by injection of Jagged1 peptide for expansion of local native stromal cells that will significantly enhance bone callus formation. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: The clinical uses of this therapeutic strategy would be immediately applicable for chronic long bone defect repair. More importantly, this devised strategy for expansion of endogenous BMSCs can also be applied to enhance other tissue and organ repair.