关于ox-LDL诱导骨髓来源的平滑肌样细胞体外转分化为泡沫样细胞的研究
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摘要
血管平滑肌细胞是动脉粥样斑块中一种主要的细胞成分,在血管疾病的发展过程中起重要作用。与终末分化的骨骼肌细胞和心肌细胞不同,成年动物体内的平滑肌细胞在局部微环境的各种因素诱导下,仍然具有高度的可塑性和可逆的表型变化特性。在早期的动脉粥样病变中,平滑肌细胞表型转化表现为平滑肌表面标志基因的表达减少、细胞增殖率升高以及细胞合成细胞外基质的增加。在动脉粥样硬化病损中,平滑肌细胞表面ox-LDL的吞噬受体表达上调能够使其转化为泡沫样细胞。虽然对中膜平滑肌细胞迁移和增殖的分子机制作了大量研究,但是至今仍然未能找到抑制血管阻塞性重建的有效治疗方法。
有研究表明骨髓间充质干细胞是平滑肌祖细胞的一个非常重要来源,这些骨髓来源的平滑肌祖细胞能够归巢到血管病损处并分化为平滑肌样细胞细胞参与冠脉搭桥术后的再狭窄、移植后再狭窄以及高脂血症所致的动脉粥样硬化等病变。但对于骨髓间充质干细胞中能够特异性分化为平滑肌系的祖细胞研究却并不多见。其原因之一为骨髓中的平滑肌祖细胞与其他几种祖细胞系同时存在,将其分离纯化存在一定困难。
虽然大量研究表明ox-LDL能够促进血管的炎症并且促进动脉粥样硬化的发生和发展,但是ox-LDL对骨髓来源的平滑肌样细胞(SMLC)的分化和转分化作用却未见报道。ox-LDL受体在骨髓来源的平滑肌样细胞(SMLC)中是否表达以及其在动脉粥样硬化中对平滑肌样细胞分化所起的作用目前仍不十分清楚。本研究旨在探讨ox-LDL受体LOX-1介导骨髓来源平滑肌样细胞的转分化作用。为骨髓源性干祖细胞在动脉粥样硬化中的作用机制提供新的实验依据。
本研究采用组织特异性启动子结合流式分选的方法,用带有SM22启动子的绿色荧光蛋白质粒重组体Psm22-eGFP-1将平滑肌祖细胞(SMPC)从骨髓间充质干细胞中分离纯化出来。分离出的平滑肌祖细胞myocardin+CD 105+KDR+CD31-CD45-CD34-,但并不表达平滑肌细胞特异性的标志物(α-SMA、SM22、smoothelin和SM-MHC)。在用PDGF-BB长时间诱导后,SMPC逐渐表达α-SMA、SM22和SM-MHC而分化为平滑肌样细胞(SMLC).当SMLC与不同浓度ox-LDL共培养之后,SMLC表面的LOX-1表达随着ox-LDL浓度升高而增多,同时myocardin和平滑肌表面特异性标志基因的表达逐渐减少。在LOX-1表达上调的同时,SMLC的吞噬功能增强,在其细胞胞浆内出现脂滴聚集,成为泡沫样细胞。
本研究表明在骨髓间充质干细胞中存在myocardin+CD 105+KDR+CD31-CD45-CD34-的平滑肌祖细胞亚群。在PDGF-BB的诱导下,这一平滑肌祖细胞亚群能够分化成为平滑肌样细胞。而且ox-LDL可通过LOX-1使其向泡沫样细胞转分化。
Vascular smooth muscle cells (SMCs) are the predominant cell type in atherosclerotic plaques and play a crucial role in the development of vascular diseases. Unlike either terminally differentiated skeletal or cardiac muscle cells, SMCs in adult animals retain remarkable plasticity and can undergo profound and reversible phenotype changes in response to various factors in their local environment. During early atherogenesis, SMCs change to a phenotype characterized by decreased expression of SMC differentiation marker proteins, a high rate of cellular proliferation, and increased synthesis of extracellular matrix proteins. The increased phagocytosis of oxidized low density lipoprotein (ox-LDL) via scavenger LDL receptor pathways in SMCs contributes to the development of foam-like cells within atherosclerotic lesions.Although much effort has been devoted to understanding the molecular pathways regulating migration and proliferation of medial SMCs, no effective therapy to prevent occlusive vascular remodeling has been established.
It has been suggested that bone marrow cells may have the potential to give rise to smooth muscle progenitor cells (SMPCs) that home to the damaged vessels and differentiate into smooth muscle-like cells (SMLCs), thereby contributing to the pathogenesis of vascular diseases. It is well known that myocardin is a CArG-dependent critical serum response factor/cofactor in the transcriptional program regulating smooth muscle cell differentiation from bone-marrow derived stem cells (BMSCs) and is required for vascular smooth muscle development. However, there have been few studies closely following the development of SMCs from BMSCs. This is due to the difficulty of isolating smooth muscle progenitor cells (SMPCs) from bulk BMSCs because SMPCs coexist with several other progenitor cells.
Oxidized low density lipoprotein (ox-LDL) is believed to contribute to atherogenesis in part by being taken up into smooth muscle cells (SMC) via specific scavenger receptors; however, it is not clear whether ox-LDL receptor(s) are expressed in bone marrow-derived smooth muscle-like cells (SMLCs) and whether they play a role in the process of SMLC development. Therefore, we examined the ox-LDL induced transdifferentiation of SMLCs that is mediated by lectin-like ox-LDL receptor-1 (LOX-1).
Smooth muscle progenitor cells (SMPCs) from bone marrow mesenchymal stem cells (BMSCs) were isolated using a tissue-specific promoter sorting method with a mouse recombinant plasmid SM22-promoter(-480bp)/green fluorescent protein. The SMPCs were myocardin+CD105+KDR+CD45-CD34-, but did not express SMC-specific markers a smooth muscle actin (α-SMA), SM22, smooth muscle myosin heavy chain (SM-MHC) and smoothelin. After long-term culture with platelet-derived growth factor-BB (PDGF-BB), SMPCs expressed a-SMA, SM22 and SM-MHC, and differentiated into SMLCs. When SMLCs were incubated with different concentrations of ox-LDL, LOX-1 expression on the surface of SMLCs gradually increased with the increase of the ox-LDL concentration, but myocardin and SMC-specific marker genes decreased, accordingly. Furthermore, receptor-mediated endocytosis was enhanced and lipid droplets accumulated in the cytoplasm of SMLCs. A subpopulation of myocardin+ CD105+KDR+ CD31+CD45-CD34- SMPCs exist in BMSCs that can differentiate into SMLCs under induction with PDGF-BB. Moreover, LOX-1 contributes to the ox-LDL-induced transdifferentiation of bone marrow-derived SMLCs into foam-like cells.
有研究表明骨髓间充质干细胞是平滑肌祖细胞的一个非常重要来源,这些骨髓来源的平滑肌祖细胞能够归巢到血管病损处并分化为平滑肌样细胞细胞参与冠脉搭桥术后的再狭窄、移植后再狭窄以及高脂血症所致的动脉粥样硬化等病变。但对于骨髓间充质干细胞中能够特异性分化为平滑肌系的祖细胞研究却并不多见。其原因之一为骨髓中的平滑肌祖细胞与其他几种祖细胞系同时存在,将其分离纯化存在一定困难。
虽然大量研究表明ox-LDL能够促进血管的炎症并且促进动脉粥样硬化的发生和发展,但是ox-LDL对骨髓来源的平滑肌样细胞(SMLC)的分化和转分化作用却未见报道。ox-LDL受体在骨髓来源的平滑肌样细胞(SMLC)中是否表达以及其在动脉粥样硬化中对平滑肌样细胞分化所起的作用目前仍不十分清楚。本研究旨在探讨ox-LDL受体LOX-1介导骨髓来源平滑肌样细胞的转分化作用。为骨髓源性干祖细胞在动脉粥样硬化中的作用机制提供新的实验依据。
本研究采用组织特异性启动子结合流式分选的方法,用带有SM22启动子的绿色荧光蛋白质粒重组体Psm22-eGFP-1将平滑肌祖细胞(SMPC)从骨髓间充质干细胞中分离纯化出来。分离出的平滑肌祖细胞myocardin+CD 105+KDR+CD31-CD45-CD34-,但并不表达平滑肌细胞特异性的标志物(α-SMA、SM22、smoothelin和SM-MHC)。在用PDGF-BB长时间诱导后,SMPC逐渐表达α-SMA、SM22和SM-MHC而分化为平滑肌样细胞(SMLC).当SMLC与不同浓度ox-LDL共培养之后,SMLC表面的LOX-1表达随着ox-LDL浓度升高而增多,同时myocardin和平滑肌表面特异性标志基因的表达逐渐减少。在LOX-1表达上调的同时,SMLC的吞噬功能增强,在其细胞胞浆内出现脂滴聚集,成为泡沫样细胞。
本研究表明在骨髓间充质干细胞中存在myocardin+CD 105+KDR+CD31-CD45-CD34-的平滑肌祖细胞亚群。在PDGF-BB的诱导下,这一平滑肌祖细胞亚群能够分化成为平滑肌样细胞。而且ox-LDL可通过LOX-1使其向泡沫样细胞转分化。
Vascular smooth muscle cells (SMCs) are the predominant cell type in atherosclerotic plaques and play a crucial role in the development of vascular diseases. Unlike either terminally differentiated skeletal or cardiac muscle cells, SMCs in adult animals retain remarkable plasticity and can undergo profound and reversible phenotype changes in response to various factors in their local environment. During early atherogenesis, SMCs change to a phenotype characterized by decreased expression of SMC differentiation marker proteins, a high rate of cellular proliferation, and increased synthesis of extracellular matrix proteins. The increased phagocytosis of oxidized low density lipoprotein (ox-LDL) via scavenger LDL receptor pathways in SMCs contributes to the development of foam-like cells within atherosclerotic lesions.Although much effort has been devoted to understanding the molecular pathways regulating migration and proliferation of medial SMCs, no effective therapy to prevent occlusive vascular remodeling has been established.
It has been suggested that bone marrow cells may have the potential to give rise to smooth muscle progenitor cells (SMPCs) that home to the damaged vessels and differentiate into smooth muscle-like cells (SMLCs), thereby contributing to the pathogenesis of vascular diseases. It is well known that myocardin is a CArG-dependent critical serum response factor/cofactor in the transcriptional program regulating smooth muscle cell differentiation from bone-marrow derived stem cells (BMSCs) and is required for vascular smooth muscle development. However, there have been few studies closely following the development of SMCs from BMSCs. This is due to the difficulty of isolating smooth muscle progenitor cells (SMPCs) from bulk BMSCs because SMPCs coexist with several other progenitor cells.
Oxidized low density lipoprotein (ox-LDL) is believed to contribute to atherogenesis in part by being taken up into smooth muscle cells (SMC) via specific scavenger receptors; however, it is not clear whether ox-LDL receptor(s) are expressed in bone marrow-derived smooth muscle-like cells (SMLCs) and whether they play a role in the process of SMLC development. Therefore, we examined the ox-LDL induced transdifferentiation of SMLCs that is mediated by lectin-like ox-LDL receptor-1 (LOX-1).
Smooth muscle progenitor cells (SMPCs) from bone marrow mesenchymal stem cells (BMSCs) were isolated using a tissue-specific promoter sorting method with a mouse recombinant plasmid SM22-promoter(-480bp)/green fluorescent protein. The SMPCs were myocardin+CD105+KDR+CD45-CD34-, but did not express SMC-specific markers a smooth muscle actin (α-SMA), SM22, smooth muscle myosin heavy chain (SM-MHC) and smoothelin. After long-term culture with platelet-derived growth factor-BB (PDGF-BB), SMPCs expressed a-SMA, SM22 and SM-MHC, and differentiated into SMLCs. When SMLCs were incubated with different concentrations of ox-LDL, LOX-1 expression on the surface of SMLCs gradually increased with the increase of the ox-LDL concentration, but myocardin and SMC-specific marker genes decreased, accordingly. Furthermore, receptor-mediated endocytosis was enhanced and lipid droplets accumulated in the cytoplasm of SMLCs. A subpopulation of myocardin+ CD105+KDR+ CD31+CD45-CD34- SMPCs exist in BMSCs that can differentiate into SMLCs under induction with PDGF-BB. Moreover, LOX-1 contributes to the ox-LDL-induced transdifferentiation of bone marrow-derived SMLCs into foam-like cells.
引文
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[2]Libby P., Theroux P. (2005) Pathophysiology of coronary artery disease. Circulation 111,3481-3488.
[3]Simper D., Stalboerger P.G., Panetta C.J., Wang S.& Caplice N.M. (2002) Smooth muscle progenitor cells in human blood. Circulation 106,1199-1204.
[4]Caplice N.M., Bunch T.J., Stalboerger P.G., Wang S., Simper D.& Miller D.V., et al. (2003) Smooth muscle cells in human coronary atherosclerosis can originate from cells administered at marrow transplantation. Proceedings of the National Academy of Sciences of the United States of America 100,4754-4759.
[5]Arakawa E., Hasegawa Yanai N., Obinata M.& Matsuda Y. (2000) A mouse bone marrow stromal cell line, TBR-B, shows inducible expression of smooth muscle-specific genes. FEBS letters 481,193-196.
[6]Yeh E.T., Zhang S., Wu H.D., Korbling M., Willerson J.T.& Estrov Z. (2003) Transdifferentiation of human peripheral blood CD34+-enriched cell population into cardiomyocytes, endothelial cells, and smooth muscle cells in vivo. Circulation 108,2070-2073.
[7]Wang D., Chang P.S., Wang Z., Sutherland L., Richardson J.A.& Small E., et al. (2001) Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell 105,851-862.
[8]Li S., Wang D.Z., Wang Z., Richardson J.A.& Olson E.N. (2003) The serum response factor coactivator myocardin is required for vascular smooth muscle development. Proceedings of the National Academy of Sciences of the United States of America 100,9366-9370.
[9]Rensen S.S., Niessen P.M., Long X., Doevendans P.A., Miano J.M.& van Eys GJ. (2006) Contribution of serum response factor and myocardin to transcriptional regulation of smoothelins. Cardiovascular research 70,136-145.
[10]Cao D., Wang Z., Zhang C.L., Oh J., Xing W.& Li S., et al. (2005) Modulation of smooth muscle gene expression by association of histone acetyltransferases and deacetylases with myocardin. Molecular and cellular biology 25,364-376.
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