PTP1B磷酸化在MSCs募集启动中调控干-龛脱离的机制研究

现有研究证实，促进宿主MSCs募集至骨缺损区是增强骨修复效应的重要技术路线。细胞迁移机制已初步阐明，但对启动募集的“干-龛脱离”机制研究甚少。干-龛脱离过程同时涉及钙黏蛋白依赖的细胞间粘附解体和整合素依赖的细胞迁移启动。我们前期研究发现PTP1B是钙黏蛋白和整合素通路交汇的枢纽，特异性抑制PTP1B Tyr152磷酸化水平可促进MSCs的钙黏蛋白粘附解体并激活整合素通路中关键的Src蛋白，另一项相关工作证实Src激活可促进MSCs募集，推测PTP1B Tyr152位点的磷酸化状态在MSCs脱龛的调控过程中发挥关键作用。本研究拟通过PTP1B的结构域模拟肽特异性抑制PTP1B Tyr152磷酸化水平，探索脱龛过程中钙黏蛋白和整合素通路的对话关系及通过促进MSCs脱龛增强募集成骨的新路径。

Enhanced MSCs recruitment to bone defect area can add bone repair. Current researches often focus on the mechanism of migration during MSCs recruitment, however, rarely focus on how can the MSCs depart from their stem cell niche, which is the crucial initial step in MSCs recruitment but remains unclear. The process of departure of MSCs from stem cell niche concerns the cadherin and integrin conducted MSCs-stem cell niche adhesion converting to the launch of integrin-dependent migration. Previously, we found tyrosine-protein phosphatase non-receptor type 1B (PTP1B) was a pivot to regulate the crosstalk between cadherin and integrin pathway. Specific inhibition of phosphorylation at PTP1B Tyr152 residue caused dissociation of cadherin adhesion complexes meanwhile activation of the important Src in the integrin pathway. Our another relative research revealed the important role of Src activation in MSCs migration. Based on those, we speculate that the phosphorylation state of PTP1B Tyr152 residue may be the core factor to regulate the departure of MSCs from its stem cell niche. This project will focus on the detailed mechanism in the converting between cadherin and integrin pathway, and propose to employ PTP1B Tyr152 region mimetic peptide to inhibit the phosphorylation of PTP1B Tyr152, which is believed to enhance MSCs recruitment to add bone repair via accelerating departure of MSCs from its stem niche.