Phosphorylation inhibition of protein-tyrosine phosphatase 1B tyrosine-152 induces bone regeneration coupled with angiogenesis for bone tissue engineering

A close relationship has been reported to exist between cadherin-mediated cell-cell adhesion and integrin-mediated cell mobility,and protein tyrosine phosphatase 1B(PTP1B)may be involved in maintaining this homeostasis.The stable residence of mesenchymal stem cells(MSCs)and endothelial cells(ECs)in their niches is closely related to the regulation of PTP1B.However,the exact role of the departure of MSCs and ECs from their niches during bone regeneration is largely unknown.Here,we show that the phosphorylation state of PTP1B tyrosine-152(Y152)plays a central role in initiating the departure of these cells from their niches and their subsequent recruitment to bone defects.Based on our previous design of a PTP1B Y152 region-mimicking peptide(152RM)that significantly inhibits the phosphorylation of PTP1B Y152,further investigations revealed that 152RM enhanced cell migration partly via integrinαvβ3 and promoted MSCs osteogenic differentiation partly by inhibiting ATF3.Moreover,152RM induced type H vessels formation by activating Notch signaling.Demineralized bone matrix(DBM)scaffolds were fabricated with mesoporous silica nanoparticles(MSNs),and 152RM was then loaded onto them by electrostatic adsorption.The DBM-MSN/152RM scaffolds were demonstrated to induce bone formation and type H vessels expansion in vivo.In conclusion,our data reveal that 152RM contributes to bone formation by coupling osteogenesis with angiogenesis,which may offer a potential therapeutic strategy for bone defects.

Fabrication of a bio-instructive scaffold conferred with a favorable microenvironment allowing for superior implant osseointegration and accelerated in situ vascularized bone regeneration via type H vessel formation

The potential translation of bio-inert polymer scaffolds as bone substitutes is limited by the lack of neovascularization upon implantation and subsequently diminished ingrowth of host bone,most likely resulted from the inability to replicate appropriate endogenous crosstalk between cells.Human umbilical vein endothelial cell-derived decellularized extracellular matrix(HdECM),which contains a collection of angiocrine biomolecules,has recently been demonstrated to mediate endothelial cells(ECs)-osteoprogenitors(OPs)crosstalk.We employed the HdECM to create a PCL(polycaprolactone)/fibrin/HdECM(PFE)hybrid scaffold.We hypothesized PFE scaffold could reconstitute a bio-instructive microenvironment that reintroduces the crosstalk,resulting in vascularized bone regeneration.Following implantation in a rat femoral bone defect,the PFE scaffold demonstrated early vascular infiltration and enhanced bone regeneration by microangiography(μ-AG)and micro-computational tomography(μ-CT).Based on the immunofluorescence studies,PFE mediated the endogenous angiogenesis and osteogenesis with a substantial number of type H vessels and osteoprogenitors.In addition,superior osseointegration was observed by a direct host bone-PCL interface,which was likely attributed to the formation of type H vessels.The bio-instructive microenvironment created by our innovative PFE scaffold made possible superior osseointegration and type H vessel-related bone regeneration.It could become an alternative solution of improving the osseointegration of bone substitutes with the help of induced type H vessels,which could compensate for the inherent biological inertness of synthetic polymers.