Phosphorylation inhibition of protein-tyrosine phosphatase 1B tyrosine-152 induces bone regeneration coupled with angiogenesis for bone tissue engineering.
Phosphorylation inhibition of protein-tyrosine phosphatase 1B tyrosine-152 induces bone regeneration coupled with angiogenesis for bone tissue engineering.
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DOI：
10.1016/j.bioactmat.2020.12.025
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发表时间：
2021-07
影响因子：
18.9
通讯作者：
Luo F
中科院分区：
文献类型：
--
作者：
Tang Y;Luo K;Chen Y;Chen Y;Zhou R;Chen C;Tan J;Deng M;Dai Q;Yu X;Liu J;Zhang C;Wu W;Xu J;Dong S;Luo F
据报道，钙粘蛋白介导的细胞间粘附和整合素介导的细胞移动性之间存在密切关系，蛋白酪氨酸磷酸酶1B（PTP 1B）可能参与维持这种稳态。间充质干细胞（mesenchymal stem cells，MSCs）和内皮细胞（endothelial cells，ECs）在其微环境中的稳定驻留与PTP 1B的调控密切相关。然而，在骨再生过程中，MSC和EC从其龛位离开的确切作用在很大程度上是未知的。在这里，我们发现PTP 1B酪氨酸-152（Y152）的磷酸化状态在启动这些细胞从其龛位出发以及随后的骨缺损招募中起着核心作用。基于我们先前设计的显著抑制PTP 1B Y152磷酸化的PTP 1B Y152区域模拟肽（152 RM），进一步研究显示152 RM部分通过整合素αvβ3促进细胞迁移，部分通过抑制ATF 3促进MSC成骨分化。此外，152 RM通过激活Notch信号通路诱导H型血管形成。以介孔二氧化硅纳米粒子（MSNs）为载体制备脱矿骨基质（DBM）支架，并通过静电吸附法将152 RM负载于其上。DBM-MSN/152 RM支架在体内具有诱导骨形成和H型血管扩张的作用。总之，我们的数据表明，152 RM有助于骨形成耦合成骨与血管生成，这可能提供一个潜在的治疗策略，骨缺损。PTP 1B在钙粘蛋白和整合素相关通路中发挥双重调节作用。PTP 1B Y152磷酸化的抑制增强了MSC从干细胞龛的离开。DBM-MSN/152 RM支架协调MSC和EC的募集。DBM-MSN/152 RM支架促进骨缺损中的骨再生和血管生成。
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 integrin αvβ3 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. PTP1B plays a dual regulatory role in cadherin- and integrin-related pathways. Inhibition of PTP1B Y152 phosphorylation enhances the departure of MSCs from the stem cell niche. DBM-MSN/152RM scaffolds coordinate the recruitment of MSCs and ECs. DBM-MSN/152RM scaffolds promote bone regeneration and angiogenesis in bone defects.
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影响因子：
8.4
作者：
Danilucci, Tais M.;Santos, Patty K.;Selistre-de-Araujo, Heloisa S.
通讯作者：
Selistre-de-Araujo, Heloisa S.
影响因子：
37.8
作者：
Lanahan AA;Lech D;Dubrac A;Zhang J;Zhuang ZW;Eichmann A;Simons M
通讯作者：
Simons M
影响因子：
15.9
作者：
Hu, Kai;Olsen, Bjorn R.
通讯作者：
Olsen, Bjorn R.
影响因子：
11.4
作者：
Acebron, Ivan;Righetto, Ricardo D.;Lietha, Daniel
通讯作者：
Lietha, Daniel
影响因子：
3.3
作者：
Hernandez, Mariana V.;Wehrendt, Diana P.;Arregui, Carlos O.
通讯作者：
Arregui, Carlos O.