不同分化状态的间充质干细胞向肝细胞生长因子的趋化性迁移研究
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摘要
神经胶质瘤是颅内最常见的恶性肿瘤,具有扩散和浸润的特性,即使经过外科手术切除,并辅以放疗或化疗,也难以彻底治愈。因此,需要新的治疗方法来追踪逃离常规治疗的散在瘤细胞。间充质干细胞(mesenchymal stem cells, MSCs)是具有多向分化潜能的成体干细胞,而且能够趋向胶质瘤及多种趋化因子迁移,从而成为治疗胶质瘤的理想载体细胞。然而MSCs定向迁移的机制还不是完全清楚,尤其是MSCs分化状态与迁移之间关系的研究还未见报道。本实验旨在研究不同分化状态的骨髓间充质干细胞(bone marrow mesenchymal stem cells, BMSCs)向肝细胞生长因子(hepatocyte growth factor, HGF)的趋化性迁移。
本研究首先采用Percoll密度梯度离心法从大鼠骨髓中分离出BMSCs,体外扩增培养,通过观察细胞形态、生长特性,免疫荧光染色,成骨、成脂诱导分化,对BMSCs进行鉴定。结果显示,分离培养的BMSCs为长梭形,增殖速度快,表面抗原CD29、CD90、CD106呈阳性,CD34、CD45为阴性,并且体外能够诱导分化为成骨细胞及脂肪细胞,证明分离培养的细胞是具有多向分化潜能的BMSCs。
随后通过丁羟基茴香醚(butyl hydroxy anisol, BHA)联合碱性成纤维生长因子(basic fibroblast growth factor, bFGF)诱导BMSCs成神经分化,即先用10 ng/ml bFGF预诱导24 h,再用200μM BHA和2% DMSO诱导5 h,最后用含有N2的H-DMEM维持培养。观察该过程中细胞的形态变化,免疫细胞化学染色检测神经细胞特异性标志物nestin、β-III-tubulin及NSE的表达变化。结果显示,未分化BMSCs呈成纤维细胞样;预诱导24 h后,胞体稍有收缩,边缘变得不齐整;诱导5 h,胞体收缩成圆形或椭圆形,折光性强,有突起伸出;维持培养18 h后,细胞出现3个或更多突起;维持培养48 h,细胞突起更为复杂,出现二级分叉,突起长度增加,与其他细胞的突起相互接触。免疫荧光染色显示,nestin与β-III-tubulin的表达都呈现出先增高后降低的趋势,均在诱导5 h时达到最高值,之后显著下降;而NSE阳性细胞比率在诱导期以及维持前期都很低,到维持48 h显著升高;GFAP在整个诱导分化过程中始终为阴性。
接着运用Dunn chamber装置研究了BMSCs及成神经分化不同状态BMSCs向HGF的趋化性迁移,计算细胞迁移速率和迁移效率。结果显示,在趋化性迁移实验中,即外槽加入不同浓度HGF、内槽只加L-DMEM时,细胞的迁移速率没有变化,迁移效率随着HGF浓度的增加而增高;与对照组(内外槽均只加入L-DMEM)相比,50 ng/ml及100 ng/ml HGF均显著提高了细胞的迁移效率,但两者之间没有差异。当内外槽均加入50 ng/ml HGF,细胞的迁移速率及迁移效率与对照相比无差异,表明HGF能够诱导BMSCs定向迁移。接着我们研究了成神经分化的BMSCs向HGF的趋化性迁移,结果显示外槽加入50 ng/ml HGF未能改变分化各点细胞的迁移速率,但显著提高了未分化、预诱导24 h、诱导5 h及维持48 h细胞的迁移效率,表明成神经分化的BMSCs向HGF的趋化迁移能力与其分化状态密切相关。用PI3K抑制剂LY294002(30μM)预处理1 h的BMSCs进行趋化迁移实验,外槽加入HGF后,细胞迁移效率与未处理组细胞相比显著降低,即LY294002阻断了HGF诱导BMSCs的定向迁移,证明PI3K信号通路参与介导HGF诱导BMSCs的定向迁移过程。
最后,通过改变Rac1的表达水平,观察BMSCs随机迁移行为及HGF诱导的定向迁移行为的变化。发现Rac1过表达后,BMSCs迁移速率及趋向HGF的迁移效率显著提高;干扰Rac1表达后,迁移速率及趋向HGF的迁移效率显著降低。结果表明Rac1调节BMSCs的迁移速率,并且参与介导HGF诱导BMSCs的定向迁移过程。
以上结果表明,HGF能够趋化BMSCs的定向迁移,PI3K信号通路参与介导这一过程;成神经分化的BMSCs趋向HGF的迁移能力与其分化状态密切相关。Rac1调节BMSCs迁移速率,并且介导HGF诱导BMSCs的定向迁移。本研究为进一步揭示BMSCs的定向迁移机制及临床应用BMSCs进行移植提供了理论基础。
Due to the infiltrating nature of tumors, the treatment of malignant gliomas invariantly fails despite extensive surgical excision and adjuvant radio- and chemo- therapy. Therefore, new therapeutic strategies are needed to selectively target tumor cells, including those that have escaped from the main tumor mass. Mesenchymal stem cells (MSCs) are adult stem cells with the capacity to differentiate into osteoblasts, chondrocytes and adipocytes. In addition, the migratory capacity of MSCs towards gliomas and several chemotatic factors has made these cells attractive therapeutic tool in gene therapy for gliomas. However, little is known about the migratory capacity of MSCs with respect to their differentiation states. The aim of our study was to characterize the migratory behavior of bone marrow mesenchymal stem cells (BMSCs) during neurogenic differentiation in response to hepatocyte growth factor (HGF).
BMSCs were isolated from bone marrow of rats by Percoll gradient centrifugation and expanded. The cells were characterized by morphology, antigen expression and differentiation potential. The results showed that BMSCs displayed fibroblast-like shape and proliferated quickly. Immunofluorescence analysis showed that BMSCs were positive for CD29, CD90, and CD106, and negative for CD34, CD45. Moreover, BMSCs were induced to differentiate into adipocytes and osteoblasts, demonstrating that these cells are multipotential BMSCs.
BMSCs were induced to neuron-like cells by basic fibroblast growth factor (bFGF) combination with butyl hydroxy anisol (BHA). The undifferentiated BMSCs were fibroblast-like. After preinductin in 10 ng/ml bFGF for 24 h, the edge of the cells became rough. Cells after 5-h induction in medium containing 2% DMSO and 200μM BHA displayed nucleus refractile cell bodies and long branching processes, with the cytoplasm retracted towards the nucleus. After maintaining in H-DMEM containing N2 for 48 h, the processes continued to elaborate, displaying primary and secondary branches, growth cone-like terminal structures that frequently made contact with other cells. Immunofluorescence staining showed that the expression of neural stem cell marker nestin and early state neuronal markerβ-III-tubulin increased and peaked at 5-h induction, and then decreased significantly, while the ratio of cells expressing NES remained low before maintaining period and increased remarkably after maintaining for 48 h. The cells were constantly GFAP negative during differentiation.
In this study, we utilized a Dunn chamber in conjunction with time-lapse video analysis to directly observe and follow the HGF-induced migration of differentiating BMSCs. The data recorded by Leica AF6000 were analyzed by NIH Image J to get migration speed and migration efficiency. The chemotaxis analysis, in which the outer well was filled with 50 ng/ml HGF and the inner well with L-DMEM only, showed that HGF did not change the migration speed of BMSCs, while the migration efficiency of BMSCs increased gradually with the increasing concentration of HGF. In contrast, neither the migration speed nor the migration efficiency was changed in the chemokinesis experiment in which both inner and outer wells were filled with 50 ng/ml HGF. The data indicate that HGF can induce the directed migration of BMSCs by chemotaxis. Next, we analyzed the chemotactic migration of BMSCs in neurogenic differentiation in response to the concentration gradients of HGF. The migration assay showed that HGF at 50 ng/ml did not change the migration speed of the cells at any state in neurongenic differentiation. However, HGF elevated the migration efficiency of undifferentiated BMSCs, and BMSCs pre-induced for 24 h, induced for 5 h and maintained for 48 h, but not those maintained for 18 h. The results indicate that the directed migration of BMSCs towards HGF is closely related to their differentiation states. To explore the role of PI3K signaling pathway in the tropism of BMSCs for HGF, the cells were pretreated for 1 h with LY294002 (30μM), a specific inhibitor of PI3K, and then used for chemotaxis assay. The data showed that the migration efficiency decreased significantly compared with untreated cells, indicating that PI3K participates in the directed migration of BMSCs to HGF.
To determine the role of Rac1 in HGF-induced migration, we altered the Rac1 expression in BMSCs and then analyzed the migratory behavior of these cells. The results showed that both the migration speed and migration efficiency were increased by up-regulation of Rac1, while decreased by down-regulation of Rac1, suggesting that Rac1 regulates the HGF-induced migration of BMSCs.
In conclusion, the isolated BMSCs from bone marrow by Percoll gradient centrifugation are multipotential and capable of differentiating into neuron-like cells by bFGF combination with BHA. HGF could induce the directional migration of BMSCs, which is mediated by the PI3K signaling pathway. In addition, the migration of cells during neurogenic differentiation towards HGF is closely related to their differentiation states. Rac1 regulates the migration speed and participates in the HGF-induced migration of BMSCs. The present study would contribute to better understanding of the directed migration of BMSCs and thus, help design strategies for the clinical applications of BMSCs.
本研究首先采用Percoll密度梯度离心法从大鼠骨髓中分离出BMSCs,体外扩增培养,通过观察细胞形态、生长特性,免疫荧光染色,成骨、成脂诱导分化,对BMSCs进行鉴定。结果显示,分离培养的BMSCs为长梭形,增殖速度快,表面抗原CD29、CD90、CD106呈阳性,CD34、CD45为阴性,并且体外能够诱导分化为成骨细胞及脂肪细胞,证明分离培养的细胞是具有多向分化潜能的BMSCs。
随后通过丁羟基茴香醚(butyl hydroxy anisol, BHA)联合碱性成纤维生长因子(basic fibroblast growth factor, bFGF)诱导BMSCs成神经分化,即先用10 ng/ml bFGF预诱导24 h,再用200μM BHA和2% DMSO诱导5 h,最后用含有N2的H-DMEM维持培养。观察该过程中细胞的形态变化,免疫细胞化学染色检测神经细胞特异性标志物nestin、β-III-tubulin及NSE的表达变化。结果显示,未分化BMSCs呈成纤维细胞样;预诱导24 h后,胞体稍有收缩,边缘变得不齐整;诱导5 h,胞体收缩成圆形或椭圆形,折光性强,有突起伸出;维持培养18 h后,细胞出现3个或更多突起;维持培养48 h,细胞突起更为复杂,出现二级分叉,突起长度增加,与其他细胞的突起相互接触。免疫荧光染色显示,nestin与β-III-tubulin的表达都呈现出先增高后降低的趋势,均在诱导5 h时达到最高值,之后显著下降;而NSE阳性细胞比率在诱导期以及维持前期都很低,到维持48 h显著升高;GFAP在整个诱导分化过程中始终为阴性。
接着运用Dunn chamber装置研究了BMSCs及成神经分化不同状态BMSCs向HGF的趋化性迁移,计算细胞迁移速率和迁移效率。结果显示,在趋化性迁移实验中,即外槽加入不同浓度HGF、内槽只加L-DMEM时,细胞的迁移速率没有变化,迁移效率随着HGF浓度的增加而增高;与对照组(内外槽均只加入L-DMEM)相比,50 ng/ml及100 ng/ml HGF均显著提高了细胞的迁移效率,但两者之间没有差异。当内外槽均加入50 ng/ml HGF,细胞的迁移速率及迁移效率与对照相比无差异,表明HGF能够诱导BMSCs定向迁移。接着我们研究了成神经分化的BMSCs向HGF的趋化性迁移,结果显示外槽加入50 ng/ml HGF未能改变分化各点细胞的迁移速率,但显著提高了未分化、预诱导24 h、诱导5 h及维持48 h细胞的迁移效率,表明成神经分化的BMSCs向HGF的趋化迁移能力与其分化状态密切相关。用PI3K抑制剂LY294002(30μM)预处理1 h的BMSCs进行趋化迁移实验,外槽加入HGF后,细胞迁移效率与未处理组细胞相比显著降低,即LY294002阻断了HGF诱导BMSCs的定向迁移,证明PI3K信号通路参与介导HGF诱导BMSCs的定向迁移过程。
最后,通过改变Rac1的表达水平,观察BMSCs随机迁移行为及HGF诱导的定向迁移行为的变化。发现Rac1过表达后,BMSCs迁移速率及趋向HGF的迁移效率显著提高;干扰Rac1表达后,迁移速率及趋向HGF的迁移效率显著降低。结果表明Rac1调节BMSCs的迁移速率,并且参与介导HGF诱导BMSCs的定向迁移过程。
以上结果表明,HGF能够趋化BMSCs的定向迁移,PI3K信号通路参与介导这一过程;成神经分化的BMSCs趋向HGF的迁移能力与其分化状态密切相关。Rac1调节BMSCs迁移速率,并且介导HGF诱导BMSCs的定向迁移。本研究为进一步揭示BMSCs的定向迁移机制及临床应用BMSCs进行移植提供了理论基础。
Due to the infiltrating nature of tumors, the treatment of malignant gliomas invariantly fails despite extensive surgical excision and adjuvant radio- and chemo- therapy. Therefore, new therapeutic strategies are needed to selectively target tumor cells, including those that have escaped from the main tumor mass. Mesenchymal stem cells (MSCs) are adult stem cells with the capacity to differentiate into osteoblasts, chondrocytes and adipocytes. In addition, the migratory capacity of MSCs towards gliomas and several chemotatic factors has made these cells attractive therapeutic tool in gene therapy for gliomas. However, little is known about the migratory capacity of MSCs with respect to their differentiation states. The aim of our study was to characterize the migratory behavior of bone marrow mesenchymal stem cells (BMSCs) during neurogenic differentiation in response to hepatocyte growth factor (HGF).
BMSCs were isolated from bone marrow of rats by Percoll gradient centrifugation and expanded. The cells were characterized by morphology, antigen expression and differentiation potential. The results showed that BMSCs displayed fibroblast-like shape and proliferated quickly. Immunofluorescence analysis showed that BMSCs were positive for CD29, CD90, and CD106, and negative for CD34, CD45. Moreover, BMSCs were induced to differentiate into adipocytes and osteoblasts, demonstrating that these cells are multipotential BMSCs.
BMSCs were induced to neuron-like cells by basic fibroblast growth factor (bFGF) combination with butyl hydroxy anisol (BHA). The undifferentiated BMSCs were fibroblast-like. After preinductin in 10 ng/ml bFGF for 24 h, the edge of the cells became rough. Cells after 5-h induction in medium containing 2% DMSO and 200μM BHA displayed nucleus refractile cell bodies and long branching processes, with the cytoplasm retracted towards the nucleus. After maintaining in H-DMEM containing N2 for 48 h, the processes continued to elaborate, displaying primary and secondary branches, growth cone-like terminal structures that frequently made contact with other cells. Immunofluorescence staining showed that the expression of neural stem cell marker nestin and early state neuronal markerβ-III-tubulin increased and peaked at 5-h induction, and then decreased significantly, while the ratio of cells expressing NES remained low before maintaining period and increased remarkably after maintaining for 48 h. The cells were constantly GFAP negative during differentiation.
In this study, we utilized a Dunn chamber in conjunction with time-lapse video analysis to directly observe and follow the HGF-induced migration of differentiating BMSCs. The data recorded by Leica AF6000 were analyzed by NIH Image J to get migration speed and migration efficiency. The chemotaxis analysis, in which the outer well was filled with 50 ng/ml HGF and the inner well with L-DMEM only, showed that HGF did not change the migration speed of BMSCs, while the migration efficiency of BMSCs increased gradually with the increasing concentration of HGF. In contrast, neither the migration speed nor the migration efficiency was changed in the chemokinesis experiment in which both inner and outer wells were filled with 50 ng/ml HGF. The data indicate that HGF can induce the directed migration of BMSCs by chemotaxis. Next, we analyzed the chemotactic migration of BMSCs in neurogenic differentiation in response to the concentration gradients of HGF. The migration assay showed that HGF at 50 ng/ml did not change the migration speed of the cells at any state in neurongenic differentiation. However, HGF elevated the migration efficiency of undifferentiated BMSCs, and BMSCs pre-induced for 24 h, induced for 5 h and maintained for 48 h, but not those maintained for 18 h. The results indicate that the directed migration of BMSCs towards HGF is closely related to their differentiation states. To explore the role of PI3K signaling pathway in the tropism of BMSCs for HGF, the cells were pretreated for 1 h with LY294002 (30μM), a specific inhibitor of PI3K, and then used for chemotaxis assay. The data showed that the migration efficiency decreased significantly compared with untreated cells, indicating that PI3K participates in the directed migration of BMSCs to HGF.
To determine the role of Rac1 in HGF-induced migration, we altered the Rac1 expression in BMSCs and then analyzed the migratory behavior of these cells. The results showed that both the migration speed and migration efficiency were increased by up-regulation of Rac1, while decreased by down-regulation of Rac1, suggesting that Rac1 regulates the HGF-induced migration of BMSCs.
In conclusion, the isolated BMSCs from bone marrow by Percoll gradient centrifugation are multipotential and capable of differentiating into neuron-like cells by bFGF combination with BHA. HGF could induce the directional migration of BMSCs, which is mediated by the PI3K signaling pathway. In addition, the migration of cells during neurogenic differentiation towards HGF is closely related to their differentiation states. Rac1 regulates the migration speed and participates in the HGF-induced migration of BMSCs. The present study would contribute to better understanding of the directed migration of BMSCs and thus, help design strategies for the clinical applications of BMSCs.
引文
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