Mesenchymal stem cell(MSC)migration determines the healing capacity of bone and is crucial in promoting bone regeneration.Migration of MSCs is highly dependent on degradation of extracellular matrix by proteolytic enz...Mesenchymal stem cell(MSC)migration determines the healing capacity of bone and is crucial in promoting bone regeneration.Migration of MSCs is highly dependent on degradation of extracellular matrix by proteolytic enzymes.However,the underlying mechanisms of how enzymolysis paves the way for MSCs to migrate from their niche to the defect area is still not fully understood.Here,this study shows that high-temperature requirement A3(HtrA3)overcomes the physical barrier and provides anchor points through collagen IV degradation,paving the way for MSC migration.HtrA3 is upregulated in MSCs at the leading edge of bone defect during the early stage of healing.HtrA3 degrades the surrounding collagen IV,which increases the collagen network porosity and increases integrinβ1 expression.Subsequently,integrinβ1 enhances the mechanotransduction of MSCs,thus remodeling the cytoskeleton,increasing cellular stiffness and nuclear translocation of YAP,eventually promoting the migration and subsequent osteogenic differentiation of MSCs.Local administration of recombinant HtrA3 in rat cranial bone defects significantly increases new bone formation and further validates the enhancement of MSC migration.This study helps to reveal the novel roles of HtrA3,explore potential targets for regenerative medicine,and offer new insights for the development of bioactive materials.展开更多
基金supported by the National Natural Science Foundation of China 81991505,U22A20160,82221003,82201123,82022016,and 52273258the National Key Research and Development Program of China 2021YFB3800800+1 种基金the Beijing Municipal Natural Science Foundation 7222226China Postdoctoral Science Foundation 2021M700279 and 2023T160029.We thank Dr.Siying Qin at the National Center for Protein Sciences of Peking University for technical help with AFM.
文摘Mesenchymal stem cell(MSC)migration determines the healing capacity of bone and is crucial in promoting bone regeneration.Migration of MSCs is highly dependent on degradation of extracellular matrix by proteolytic enzymes.However,the underlying mechanisms of how enzymolysis paves the way for MSCs to migrate from their niche to the defect area is still not fully understood.Here,this study shows that high-temperature requirement A3(HtrA3)overcomes the physical barrier and provides anchor points through collagen IV degradation,paving the way for MSC migration.HtrA3 is upregulated in MSCs at the leading edge of bone defect during the early stage of healing.HtrA3 degrades the surrounding collagen IV,which increases the collagen network porosity and increases integrinβ1 expression.Subsequently,integrinβ1 enhances the mechanotransduction of MSCs,thus remodeling the cytoskeleton,increasing cellular stiffness and nuclear translocation of YAP,eventually promoting the migration and subsequent osteogenic differentiation of MSCs.Local administration of recombinant HtrA3 in rat cranial bone defects significantly increases new bone formation and further validates the enhancement of MSC migration.This study helps to reveal the novel roles of HtrA3,explore potential targets for regenerative medicine,and offer new insights for the development of bioactive materials.
