TGFβ3 recruits endogenous mesenchymal stem cells to initiate bone regeneration.
TGFβ3 recruits endogenous mesenchymal stem cells to initiate bone regeneration.
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TGF beta 3 招募内源性间充质干细胞启动骨再生
DOI：
10.1186/s13287-017-0693-0
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发表时间：
2017-11-10
影响因子：
7.5
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Deng M;Mei T;Hou T;Luo K;Luo F;Yang A;Yu B;Pang H;Dong S;Xu J
募集足够数量的内源性间充质干细胞（MSCs）是原位组织再生的第一步。转化生长因子β -3 （tgf - β3）可以募集干细胞、祖细胞和内皮细胞参与组织再生。然而，tgf - β3募集MSCs促进骨再生的机制尚不清楚。采用Transwell法测定tgf - β3对与血管细胞（人脐动脉平滑肌细胞或人脐静脉内皮细胞）共培养的人骨髓间充质干细胞（hBMSCs）的促迁移特性。加入抑制剂（SB431542）或Smad3 siRNA后，用ELISA试剂盒检测共培养培养基中MCP1和SDF1的水平，然后用western blot分析TGFβ3诱导hBMSCs的迁移信号通路。在体内，采用2mm FVB/N小鼠股骨缺损模型，通过qPCR、免疫荧光染色、免疫组织化学分析和Micro-CT，与载tgf - β3组比较，评价载tgf - β3 1 μg支架诱导趋化因子分泌、内源性细胞归巢和骨再生。tgf - β3 （25 ng/ml）通过tgf - β信号通路直接显示迁移的hBMSCs比载体处理增加近40%。然后，在hBMSCs和血管细胞共培养系统中，tgf - β3进一步以smad3依赖的方式上调血管细胞近3倍的MCP1分泌，间接增强了近50%以上的迁移hBMSCs。在体内，tgf - β3递送使MCP1表达提高了近7.9倍，募集了约2.0倍的CD31+血管细胞和2.0倍的ca-1+ PDGFR-α+ MSCs，实现了2.5倍的骨体积分数（BV/TV）和2.0倍的骨矿物质密度，相对于tgf - β3递送。tgf - β3作为MSC归巢分子，通过直接依赖和间接依赖的机制募集MSCs启动骨形成。这可能有助于改善骨髓间充质干细胞在骨再生中的归巢作用。
The recruitment of a sufficient number of endogenous mesenchymal stem cells (MSCs) is the first stage of in-situ tissue regeneration. Transforming growth factor beta-3 (TGFβ3) could recruit stem or progenitor cells and endothelial cells to participate in tissue regeneration. However, the mechanism of TGFβ3 recruiting MSCs toward bone regeneration has remained obscure. We estimated the promigratory property of TGFβ3 on human bone marrow MSCs (hBMSCs) cocultured with the vascular cells (human umbilical artery smooth muscle cells or human umbilical vein endothelial cells) or not by Transwell assay. After the addition of the inhibitor (SB431542) or Smad3 siRNA, the levels of MCP1 and SDF1 in coculture medium were tested by ELISA kit, and then the migratory signaling pathway of hBMSCs induced by TGFβ3 was investigated by western blot analysis. In vivo, a 2-mm FVB/N mouse femur defect model was used to evaluate chemokine secretion, endogenous cell homing, and bone regeneration induced by scaffolds loading 1 μg TGFβ3 through qPCR, immunofluorescent staining, immunohistochemical analysis, and Micro-CT, compared to the vehicle group. TGFβ3 (25 ng/ml) directly showed a nearly 40% increase in migrated hBMSCs via the TGFβ signaling pathway, compared to the vehicle treatment. Then, in the coculture system of hBMSCs and vascular cells, TGFβ3 further upregulated nearly 3-fold MCP1 secretion from vascular cells in a Smad3-dependent manner, to indirectly enhance nearly more than 50% of migrated hBMSCs. In vivo, TGFβ3 delivery improved MCP1 expression by nearly 7.9-fold, recruited approximately 2.0-fold CD31+ vascular cells and 2.0-fold Sca-1+ PDGFR-α+ MSCs, and achieved 2.5-fold bone volume fraction (BV/TV) and 2.0-fold bone mineral density, relative to TGFβ3-free delivery. TGFβ3, as a MSC homing molecule, recruited MSCs to initiate bone formation in the direct-dependent and indirect-dependent mechanisms. This may shed light on the improvement of MSC homing in bone regeneration.
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