TLX基因对大鼠真皮多能干细胞增殖和成神经细胞分化及移植治疗脊髓损伤的影响研究
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摘要
TLX基因最初是作为一个“孤儿”核受体发现的,其功能不明。但近来研究结果表明,TLX基因在神经系统发育过程中具有重要意义,是维持成体干细胞增殖和成神经分化的关键基因。
脊髓损伤(Spinal Cord Injury, SCI)后神经细胞再生能力不足是影响损伤脊髓功能恢复的关键,神经细胞的再生问题一直是困扰神经科学工作者的大难题。目前可用于治疗脊髓损伤的种子细胞来源主要包括:胚胎来源干细胞;来源于神经系统的具有促神经再生作用的细胞;其他具有成神经分化潜能的成体干细胞。胚胎干细胞具有分化全能性和无限增殖的能力,进行成神经诱导分化后用于脊髓损伤治疗时具有替代受损神经元、重建神经元回路的作用,但考虑到伦理学、法律学、组织相容性以及胚胎的来源等难题,其临床应用目前还受到限制。多种来源于神经系统的细胞在脊髓损伤时可作为种子细胞,具有促神经功能恢复作用,但这些细胞在成年个体中数量较少,增殖能力较为有限,并且取材困难,行自体移植时尤为明显;而进行异体移植则要面临组织相容性和免疫相斥等难题。近来多种具有成神经分化潜能的间充质干细胞在脊髓损伤中的研究受到了关注,并有望为脊髓损伤治疗提供新的种子细胞来源。因此,研究真皮多能干细胞高效定向成神经分化的机制及调控将为解决脊髓移植供体细胞来源探索新的途径。基因治疗也是一种促进脊髓损伤再生的有希望的措施,基因修饰DMSCs移植则是结合了两者的优点。
为了确定TLX基因对DMSCs增殖和成神经细胞分化的影响以及TLX基因工程化DMSCs对SCI后神经再生和功能修复的影响,本文就此进行了系列研究。⑴大鼠TLX基因的克隆及含TLX基因的全长编码序列的真核表达载体的构建和表达;⑵观察大鼠TLX基因对DMSCs的增殖和成神经分化的影响;⑶将TLX基因修饰DMSCs移植到大鼠脊髓全横断模型的损伤部位,观察移植物能否促进脊髓功能的恢复,来阐明TLX基因修饰DMSCs在SCI恢复中所起的作用。希望通过移植物(TLX基因修饰DMSCs)恒定表达TLX,使移植区具有高浓度的TLX,通过TLX高效、定向诱导DMSCs分化为神经细胞,可能为SCI再生修复提供更合适的种子细胞。主要结果如下:
1、利用设计合成的TLX简并引物,以成年大鼠大脑组织总RNA为模板,进行RT-PCR,我们首次成功扩增出大鼠TLX全长编码序列,序列在线BLAST发现,其与大鼠预测的TLX序列99%相似,证实扩增和克隆成功,将大鼠TLX序列登陆GeneBank,获得Gene accession number:EU316216。
2、利用RT-PCR的产物,采用定向克隆的方法,先进行T/A克隆,然后成功地将TLX cDNA全长序列亚克隆到pEGFPN1真核表达载体上。在此基础上,将重组质粒pEGFPN1-TLX转染到DMSCs中,用荧光显微镜下观察到荧光蛋白的表达和用RT-PCR方法检测到TLXmRNA的表达,说明TLX已成功转染DMSCs并能在DMSCs中表达。
3、MTT法研究显示TLX可以促进DMSCs的增殖;DMSCs经诱导后可分化成神经细胞,分化出来的细胞中,星形胶质细胞的比例较高,而神经元比例较低。TLX可以促进DMSCs向神经元方向分化,TLX/DMSCs分化出来的细胞中,与未转染TLX的DMSCs相比,神经元的比例明显增高,而星形胶质细胞比例降低。
4、将DMSCs和TLX基因修饰DMSCs移植入大鼠脊髓全横断处,结果显示DMSCs和TLX基因修饰DMSCs都能在宿主脊髓内存活和整合,并使脊髓形态学结构达到部分恢复;行为学检测检测显示大鼠脊髓运动功能得到部分恢复,其中移植TLX基因修饰DMSCs使大鼠的功能恢复更好一些。
综上所述,我们首次成功的地扩增出大鼠TLX基因并构建了含TLX基因全长编码序列的真核表达载体。进一步研究显示TLX基因可以促进DMSCs增殖和向神经元方向分化,抑制DMSCs向星形胶质细胞的分化;移植TLX基因修饰DMSCs可以促进大鼠脊髓损伤后功能和形态的部分恢复,表现为行为学评分明显增高、损伤区空洞和瘢痕面积缩小和通过损伤区的神经纤维数量增多,与移植单纯DMSCs相比较,移植TLX基因修饰的DMSCs治疗效果要显著一些。结果提示TLX基因可能通过提高DMSCs向神经元分化而抑制星形胶质细胞的产生、减少胶质瘢痕形成具有促进脊髓损伤后神经再生和功能重建的作用,为临床治疗脊髓损伤提供新思路。
TLX belongs to a class of orphan nuclear receptors that underlies many aspects of neural development in the CNS. TLX gene was expressing in vertebrates forebrain during embryogenesis, it can help maintaining neural progenitor cells quantities and play an important role in its differentiation into neurons,TLX gene knock-out mice its neural progenitor cells proliferative state and differentiation into neuronsability were influenced. TLX also underlies a fundamental developmental program of retinal organization and controls the generation of the proper numbers of retinal progenies and development of glial cells during the protracted period of retinogenesis. In addition, TLX gene can significantly inhibit expression of the astroglial marker glia fibrillary acidic protein (GFAP) in neural stem cells.
Many stem cells such as ESCs and NSCs can be used to treat a lot of neurological disease. But the use of embryonic stem cells ESC may raise ethical issues and practical problems such as the fate of the embryonic cells in adult environment and the required immunosuppression. NSCs transplantation, indeed, is limited by the inaccessibility of its source, that is located deeply in the brain. Therefore the identification of a readily accessible source of neural cells obtainable without invasive procedures could be of a great benefit. Several non-neuronal tissues can be a source of adult stem cells capable of neuronal differentiation. Recently it has been shown that dermal multipotential stem cells is present in the dermis of mammalian skin, and if grown in vitro it preferentially forms floating spheres constituted by cells positive for fibronectin and nestin. After long term and continuous cultured, dermal multipotential stem cells maintain highly proliferative and differentiative ability, which suggests that DMSCs is a perfect“seed”cells in cell substitute therapy.
Both the absence of neuronal regeneration ability and local environment factor in spinal cord injury are harmful to the repairment of injuried spinal cord tissues. The recovery of spinal cord after injury is all along a difficult problem that puzzles the neuroscientists. Numerious studies had been carried out by neuroscientists, and some encourage results had been obtained. Dermal multipotential stem cells (DMSCs) transplantation had been a prospect treatment for spinal cord injury (SCI). Deliveries of therapeutic genes are also new and promising strategies to simulate regeneration of spinal cord after injury. DMSCs engineered by gene combines the therapeutic values of DMSCs transplantation and gene delivery.
In order to determin the effects of TLX gene on the proliferation and differentiation into neurons of DMSCs and see if the DMSCs and DMSCs engineered by TLX gene have the effects of promoting the regeneration and function recovery of SCI, a series of studies were carried out as follows: (1)clone rat TLX CDS sequence and built pEGFPN1 vector containing TLX gene complete CDS sequence, and examined its expression; (2)explored effects of TLX in proliferation and differentiation into neurons of DMSCs; (3) transplanted DMSCs modified by TLX gene into the area of spinal cord transverse in rats, explored effects of transplantation on promoting function recovery of spinal cord, and clarified roles of DMSCs modified by TLX gene on recovery of SCI in rats. We hope that the transplantation material- DMSCs modified by TLX gene express TLX protein eternally, and provide a possible agreeable microenvironment for regeneration and recovery of spinal cord after injury. The main results are as following:
1. In this study, rat TLX full length CDS sequence was amplificatied through Reversetranscription-PCR(RT-PCR), the TLX degenerate primers were used and the total RNA in adult rat brain was the amplificative templet. Basic local alignment search tool (BLAST) search online found that the sequence was 99% similarity to the rat TLX predicted sequence. It suggested that we successfully cloned the rat TLX gene. The sequence was submitted to GeneBank , We get a Gene accession number:EU316216.
2. Using RT-PCR product, the TLX cDNA was cloned to pMD18-T, then identified pMD18-T-TLX by double enzyme cutting by means of restriction enzyme BamHI and HindⅢ,and then the TLX fragment second-cloned to lined pEGFPN1. Then the pEGFPN1- TLX was transferred to DMSCs. The GFP expression and TLX expression was detected with fluorescence microscope and RT-PCR respectively. The results suggests that pEGFPN1-TLX was successfully constructed .In adition, the result of RT-PCR indicates that the TLX was successfully transferred to DMSCs and expressed in DMSCs.
3. Using MTT we conclude that TLX can promote the proliferation of DMSCs;When DMSCs differentiated in vitro, DMSCs can be differentiated into neurons and astrocytes, and the the percent of astrocytes was higher than neuons,While DMSCs modified by TLX gene differentiated, the percent of neurons increased. TLX helped the differentiation of DMSCs to neurons, but the percent of astrocytes decreased.
4. DMSCs and DMSCs modified by TLX gene were transplanted into spinal cord transverse injured site. The results indicated that DMSCs and DMSCs modified by TLX gene survived and integrated into the host spinal cord, the structure and fuction of spinal cord were recovered partially. It seems that transplantations promoted partial recovery of motor functions of spinal cord, and the effects of DMSCs modified by TLX gene group seems better than that of the DMSCs group.
In summary, we successfully cloned the rat TLX gene. The sequence was submitted to GeneBank , We get a Gene accession number:EU316216. And then we built pEGFPN1 vector containing TLX gene complete sequence. Results showed TLX gene promoted the proliferation and the differentiation of DMSCs to neurons and inhibited the differentiation of DMSCs to astrocytes. The transplantation of DMSCs and DMSCs modified by TLX gene promoted recovery of structure and function of spinal cord after injury, the effects of DMSCs modified by TLX gene were a litter better than that of DMSCs. Our results indicated that TLX gene probably involved in the processs of repair of spinal cord and rebuilding of function through helped the differentiation of DMSCs to neurons and inhibited the differentiation to astrocytes. The results of this study provide some fundmental information for the clinical application of SCI..
脊髓损伤(Spinal Cord Injury, SCI)后神经细胞再生能力不足是影响损伤脊髓功能恢复的关键,神经细胞的再生问题一直是困扰神经科学工作者的大难题。目前可用于治疗脊髓损伤的种子细胞来源主要包括:胚胎来源干细胞;来源于神经系统的具有促神经再生作用的细胞;其他具有成神经分化潜能的成体干细胞。胚胎干细胞具有分化全能性和无限增殖的能力,进行成神经诱导分化后用于脊髓损伤治疗时具有替代受损神经元、重建神经元回路的作用,但考虑到伦理学、法律学、组织相容性以及胚胎的来源等难题,其临床应用目前还受到限制。多种来源于神经系统的细胞在脊髓损伤时可作为种子细胞,具有促神经功能恢复作用,但这些细胞在成年个体中数量较少,增殖能力较为有限,并且取材困难,行自体移植时尤为明显;而进行异体移植则要面临组织相容性和免疫相斥等难题。近来多种具有成神经分化潜能的间充质干细胞在脊髓损伤中的研究受到了关注,并有望为脊髓损伤治疗提供新的种子细胞来源。因此,研究真皮多能干细胞高效定向成神经分化的机制及调控将为解决脊髓移植供体细胞来源探索新的途径。基因治疗也是一种促进脊髓损伤再生的有希望的措施,基因修饰DMSCs移植则是结合了两者的优点。
为了确定TLX基因对DMSCs增殖和成神经细胞分化的影响以及TLX基因工程化DMSCs对SCI后神经再生和功能修复的影响,本文就此进行了系列研究。⑴大鼠TLX基因的克隆及含TLX基因的全长编码序列的真核表达载体的构建和表达;⑵观察大鼠TLX基因对DMSCs的增殖和成神经分化的影响;⑶将TLX基因修饰DMSCs移植到大鼠脊髓全横断模型的损伤部位,观察移植物能否促进脊髓功能的恢复,来阐明TLX基因修饰DMSCs在SCI恢复中所起的作用。希望通过移植物(TLX基因修饰DMSCs)恒定表达TLX,使移植区具有高浓度的TLX,通过TLX高效、定向诱导DMSCs分化为神经细胞,可能为SCI再生修复提供更合适的种子细胞。主要结果如下:
1、利用设计合成的TLX简并引物,以成年大鼠大脑组织总RNA为模板,进行RT-PCR,我们首次成功扩增出大鼠TLX全长编码序列,序列在线BLAST发现,其与大鼠预测的TLX序列99%相似,证实扩增和克隆成功,将大鼠TLX序列登陆GeneBank,获得Gene accession number:EU316216。
2、利用RT-PCR的产物,采用定向克隆的方法,先进行T/A克隆,然后成功地将TLX cDNA全长序列亚克隆到pEGFPN1真核表达载体上。在此基础上,将重组质粒pEGFPN1-TLX转染到DMSCs中,用荧光显微镜下观察到荧光蛋白的表达和用RT-PCR方法检测到TLXmRNA的表达,说明TLX已成功转染DMSCs并能在DMSCs中表达。
3、MTT法研究显示TLX可以促进DMSCs的增殖;DMSCs经诱导后可分化成神经细胞,分化出来的细胞中,星形胶质细胞的比例较高,而神经元比例较低。TLX可以促进DMSCs向神经元方向分化,TLX/DMSCs分化出来的细胞中,与未转染TLX的DMSCs相比,神经元的比例明显增高,而星形胶质细胞比例降低。
4、将DMSCs和TLX基因修饰DMSCs移植入大鼠脊髓全横断处,结果显示DMSCs和TLX基因修饰DMSCs都能在宿主脊髓内存活和整合,并使脊髓形态学结构达到部分恢复;行为学检测检测显示大鼠脊髓运动功能得到部分恢复,其中移植TLX基因修饰DMSCs使大鼠的功能恢复更好一些。
综上所述,我们首次成功的地扩增出大鼠TLX基因并构建了含TLX基因全长编码序列的真核表达载体。进一步研究显示TLX基因可以促进DMSCs增殖和向神经元方向分化,抑制DMSCs向星形胶质细胞的分化;移植TLX基因修饰DMSCs可以促进大鼠脊髓损伤后功能和形态的部分恢复,表现为行为学评分明显增高、损伤区空洞和瘢痕面积缩小和通过损伤区的神经纤维数量增多,与移植单纯DMSCs相比较,移植TLX基因修饰的DMSCs治疗效果要显著一些。结果提示TLX基因可能通过提高DMSCs向神经元分化而抑制星形胶质细胞的产生、减少胶质瘢痕形成具有促进脊髓损伤后神经再生和功能重建的作用,为临床治疗脊髓损伤提供新思路。
TLX belongs to a class of orphan nuclear receptors that underlies many aspects of neural development in the CNS. TLX gene was expressing in vertebrates forebrain during embryogenesis, it can help maintaining neural progenitor cells quantities and play an important role in its differentiation into neurons,TLX gene knock-out mice its neural progenitor cells proliferative state and differentiation into neuronsability were influenced. TLX also underlies a fundamental developmental program of retinal organization and controls the generation of the proper numbers of retinal progenies and development of glial cells during the protracted period of retinogenesis. In addition, TLX gene can significantly inhibit expression of the astroglial marker glia fibrillary acidic protein (GFAP) in neural stem cells.
Many stem cells such as ESCs and NSCs can be used to treat a lot of neurological disease. But the use of embryonic stem cells ESC may raise ethical issues and practical problems such as the fate of the embryonic cells in adult environment and the required immunosuppression. NSCs transplantation, indeed, is limited by the inaccessibility of its source, that is located deeply in the brain. Therefore the identification of a readily accessible source of neural cells obtainable without invasive procedures could be of a great benefit. Several non-neuronal tissues can be a source of adult stem cells capable of neuronal differentiation. Recently it has been shown that dermal multipotential stem cells is present in the dermis of mammalian skin, and if grown in vitro it preferentially forms floating spheres constituted by cells positive for fibronectin and nestin. After long term and continuous cultured, dermal multipotential stem cells maintain highly proliferative and differentiative ability, which suggests that DMSCs is a perfect“seed”cells in cell substitute therapy.
Both the absence of neuronal regeneration ability and local environment factor in spinal cord injury are harmful to the repairment of injuried spinal cord tissues. The recovery of spinal cord after injury is all along a difficult problem that puzzles the neuroscientists. Numerious studies had been carried out by neuroscientists, and some encourage results had been obtained. Dermal multipotential stem cells (DMSCs) transplantation had been a prospect treatment for spinal cord injury (SCI). Deliveries of therapeutic genes are also new and promising strategies to simulate regeneration of spinal cord after injury. DMSCs engineered by gene combines the therapeutic values of DMSCs transplantation and gene delivery.
In order to determin the effects of TLX gene on the proliferation and differentiation into neurons of DMSCs and see if the DMSCs and DMSCs engineered by TLX gene have the effects of promoting the regeneration and function recovery of SCI, a series of studies were carried out as follows: (1)clone rat TLX CDS sequence and built pEGFPN1 vector containing TLX gene complete CDS sequence, and examined its expression; (2)explored effects of TLX in proliferation and differentiation into neurons of DMSCs; (3) transplanted DMSCs modified by TLX gene into the area of spinal cord transverse in rats, explored effects of transplantation on promoting function recovery of spinal cord, and clarified roles of DMSCs modified by TLX gene on recovery of SCI in rats. We hope that the transplantation material- DMSCs modified by TLX gene express TLX protein eternally, and provide a possible agreeable microenvironment for regeneration and recovery of spinal cord after injury. The main results are as following:
1. In this study, rat TLX full length CDS sequence was amplificatied through Reversetranscription-PCR(RT-PCR), the TLX degenerate primers were used and the total RNA in adult rat brain was the amplificative templet. Basic local alignment search tool (BLAST) search online found that the sequence was 99% similarity to the rat TLX predicted sequence. It suggested that we successfully cloned the rat TLX gene. The sequence was submitted to GeneBank , We get a Gene accession number:EU316216.
2. Using RT-PCR product, the TLX cDNA was cloned to pMD18-T, then identified pMD18-T-TLX by double enzyme cutting by means of restriction enzyme BamHI and HindⅢ,and then the TLX fragment second-cloned to lined pEGFPN1. Then the pEGFPN1- TLX was transferred to DMSCs. The GFP expression and TLX expression was detected with fluorescence microscope and RT-PCR respectively. The results suggests that pEGFPN1-TLX was successfully constructed .In adition, the result of RT-PCR indicates that the TLX was successfully transferred to DMSCs and expressed in DMSCs.
3. Using MTT we conclude that TLX can promote the proliferation of DMSCs;When DMSCs differentiated in vitro, DMSCs can be differentiated into neurons and astrocytes, and the the percent of astrocytes was higher than neuons,While DMSCs modified by TLX gene differentiated, the percent of neurons increased. TLX helped the differentiation of DMSCs to neurons, but the percent of astrocytes decreased.
4. DMSCs and DMSCs modified by TLX gene were transplanted into spinal cord transverse injured site. The results indicated that DMSCs and DMSCs modified by TLX gene survived and integrated into the host spinal cord, the structure and fuction of spinal cord were recovered partially. It seems that transplantations promoted partial recovery of motor functions of spinal cord, and the effects of DMSCs modified by TLX gene group seems better than that of the DMSCs group.
In summary, we successfully cloned the rat TLX gene. The sequence was submitted to GeneBank , We get a Gene accession number:EU316216. And then we built pEGFPN1 vector containing TLX gene complete sequence. Results showed TLX gene promoted the proliferation and the differentiation of DMSCs to neurons and inhibited the differentiation of DMSCs to astrocytes. The transplantation of DMSCs and DMSCs modified by TLX gene promoted recovery of structure and function of spinal cord after injury, the effects of DMSCs modified by TLX gene were a litter better than that of DMSCs. Our results indicated that TLX gene probably involved in the processs of repair of spinal cord and rebuilding of function through helped the differentiation of DMSCs to neurons and inhibited the differentiation to astrocytes. The results of this study provide some fundmental information for the clinical application of SCI..
引文
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