Ischemic injury causes dynamic damage to the native extracellular matrix(ECM),which plays a key role in tissue homeo-stasis and regeneration by providing structural support,facilitating force transmission,and transduc...Ischemic injury causes dynamic damage to the native extracellular matrix(ECM),which plays a key role in tissue homeo-stasis and regeneration by providing structural support,facilitating force transmission,and transducing key signals to cells.The main approach aimed at repairing injury to ischemic tissues is restoration of vascular function.Due to their potential to form capillary niches,endothelial cells(ECs)are of greatest interest for vascular regeneration.Integrin binding to ECM is crucial for cell anchorage to the surrounding matrix,spreading,migration,and further activation of intracellular signaling pathways.In this study,we proposed to establish an in-situ engineering strategy to remodel the ECM at the ischemic site to guide EC endogenous binding and establish effective EC/ECM interactions to promote revascularization.We designed and constructed a dual-function molecule(LXW7)2-SILY,which is comprised of two functional domains:the first one(LXW7)binds to integrinαvβ3 expressed on ECs,and the second one(SILY)binds to collagen.In vitro,we confirmed(LXW7)2-SILY improved EC adhesion and survival.After in situ injection,(LXW7)2-SILY showed stable retention at the injured area and promoted revascularization,blood perfusion,and tissue regeneration in a mouse hindlimb ischemia model.展开更多
基金supported by NIH grants(R01NS100761,R01NS115860 and R21HD107324)Department of Defense’s Congressionally Directed Medical Research Program(PR221734P1)+2 种基金Shriners Children’s grants(87300-NCA-24,85220-NCA-24,85400-NCA-24)American Heart Association grant(24TPA1288860)California Institute for Regenerative Medicine(CIRM)grant(TRAN3-13332).Utilization of the Combinatorial Chemistry and Chemical Biology Shared Resource was supported by the UC Davis Comprehensive Cancer Center Support Grant awarded by the National Cancer Institute(P30CA093373).
文摘Ischemic injury causes dynamic damage to the native extracellular matrix(ECM),which plays a key role in tissue homeo-stasis and regeneration by providing structural support,facilitating force transmission,and transducing key signals to cells.The main approach aimed at repairing injury to ischemic tissues is restoration of vascular function.Due to their potential to form capillary niches,endothelial cells(ECs)are of greatest interest for vascular regeneration.Integrin binding to ECM is crucial for cell anchorage to the surrounding matrix,spreading,migration,and further activation of intracellular signaling pathways.In this study,we proposed to establish an in-situ engineering strategy to remodel the ECM at the ischemic site to guide EC endogenous binding and establish effective EC/ECM interactions to promote revascularization.We designed and constructed a dual-function molecule(LXW7)2-SILY,which is comprised of two functional domains:the first one(LXW7)binds to integrinαvβ3 expressed on ECs,and the second one(SILY)binds to collagen.In vitro,we confirmed(LXW7)2-SILY improved EC adhesion and survival.After in situ injection,(LXW7)2-SILY showed stable retention at the injured area and promoted revascularization,blood perfusion,and tissue regeneration in a mouse hindlimb ischemia model.
