去分化表皮细胞重获再生表皮能力的研究
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摘要
一、研究背景和目的
较大面积重度的全身烧创伤患者，通过皮肤移植等常规手术方法，几乎无一避免会出现创面瘢痕愈合的结局。虽然表皮干细胞对于严重创面修复的组织工程学具有重要帮助，但重度全身烧伤患者残存的正常皮肤很少，正常皮肤的表皮干细胞数量本身就很有限，只占正常表皮基底层的1%-10%，干细胞数量远达不到修复上述创面的要求，显然这会明显限制干细胞组织工程技术在临床上的广泛应用。是否有可以解决表皮干细胞短缺，获得足量的表皮干细胞将其移植到创面，最终可能实现创面的“完美修复”这样的方法呢？
去分化就是获得大量成体干细胞的途径之一，表皮细胞存在去分化现象。已分化成熟的终末分化表皮细胞通过去分化可以反向分成他们的父辈细胞，也就是说，表皮细胞可以从“年老的”分化状态返回到“年轻的”不完全分化、甚至具有表皮干细胞特征的幼稚状态的过程。而这些去分化来源的“年轻”细胞可用于上述创面治疗。我们如何主动地将已分化细胞在体外为诱导成为分化程度较低形式的细胞，甚至分化程度更低的再生皮肤能力更强的表皮干细胞呢？
答案是肯定的。有报道，某些特定因素可以诱导表皮细胞去分化。因此，建立可靠而稳定的去分化方法将从根本上解决上述疾病治疗面临的表皮干细胞数量短缺的严重问题。去分化方法是一符合道德、伦理规范的替代方案，没有遗传不相容和组织排斥风险。
成熟细胞去分化时涉及几条复杂的信号通路，如Wnt/β-连环蛋白、p38、细胞外信号调节激酶（ERK）和Janus激酶（JAK）/信号转导和转录激活因子（STAT）信号通路。但尚未有研究报告诱导分化表皮细胞退回到有再生能力不成熟状态的通路。越来越多的证据表明，Wnt信号转导对于皮肤的正常发育十分必要，Wnt信号通路的关键效应器是参与维持皮肤祖细胞群的β-连环蛋白。研究亦表明，β-连环蛋白水平升高会导致表皮干细胞增生并诱导细胞转分化为毛囊干细胞。
本研究第一部分是在前期表皮干细胞工作基础上，继续探讨并确立稳定的表皮干细胞培养体系，为深入去分化研究奠定基础。第二部分特别针对性探讨β-连环蛋白活化对于分化表皮细胞特性的影响。首先应用氯化锂（LiCl）和高度特异性GSK-3β抑制剂诱导β-连环蛋白表达，然后针对β-连环蛋白活化对于去分化细胞的形态、表型和生长特性的影响进行观察，最后对比去分化细胞体外再生表皮的能力。
二、方法
新鲜人包皮片前期处理后，用中性蛋白水解酶分离得到表皮，制成单细胞悬液，用差速贴壁法移去已分化表皮细胞，光镜和电镜下观察表皮干细胞的特点，并使用表皮干细胞标记物鉴定。利用差速贴壁法从表皮片中分离出人体表皮细胞接种于6孔板并分为3组，即对照组（无处理组），LiCl处理组和GSK-3β抑制剂处理组。应用LiCl和高度特异性GSK-3β抑制剂活化β-连环蛋白表达，针对β-连环蛋白活化对于去分化细胞的形态、表型和生长特性的影响观察，并对比细胞体外再生表皮的能力。
三、结果
差速贴壁法分离表皮得到的表皮干细胞具有干细胞的形态特点，光镜下细胞贴壁生长，由小圆珠状渐成方形的铺路石状。电镜下核大，细胞器少，为典型非成熟细胞。2周后原代细胞铺满瓶底。用含生长促进因子的DMEM/F12培养的表皮干细胞24h即可伸展贴壁和伸展，原代细胞3-4d即铺满瓶底。原代培养的表皮干细胞免疫组化显示表皮干细胞的系列表面标记物，不表达已分化表皮细胞的标记物CK10。
3组细胞中，免疫印迹和光动力学分析显示β-连环蛋白在LiCl组和GSK-3β抑制剂组表皮细胞核内的表达较未处理组显著增高。培养3、6d时，倒置相差显微镜下见两处理组细胞表现为表皮干细胞的典型变化。免疫组化分析表明两处理组CK10表达的数量和比例均显著下降，而表皮干细胞的标记物CK19和β1整合素的表达加强。与对照组相比，Oct4和Nanog基因在去分化的处理组细胞中高4-6倍。3d时两处理组已明显的集落形成，而对照组生长稀疏。流式细胞仪检测出的细胞周期数据表明两处理组中有较多细胞处于增殖期，且与对照组有显著差异。持续传代培养表明两处理组有更强的远期增殖潜能。培养11d后，对照组未成表皮单层，但处理组和表皮干细胞组在真皮替代物表面再生了复层表皮。
四、结论
采用中性蛋白酶选择性的水解真皮和表皮之间的细胞连接，再用差速贴壁法分离表皮干细胞是一种高效的表皮干细胞获取方法。含10%FBS低糖DMEM/F12是可以保持表皮干细胞去分化状态的良好培养基。
表皮细胞在分化后能够因β-连环蛋白的表达增加而重新恢复表皮干细胞的特征。LiCl和GSK-3β抑制剂处理可引起分化后表皮细胞胞核中的β-连环蛋白表达增加。去分化细胞表皮能表现出干细胞的形态、表型和生长特性。此外，去分化的细胞所再生的表皮与表皮干细胞所产生的类似。实验结果表明，通过调控β-连环蛋白的表达实现高效的去分化过程可产生丰富的表皮干细胞。Wnt/β-连环蛋白信号通路对皮肤创面修复与再生起着重要作用。
Background and Objectives
Scar outcome will inevitably appear in patients with severe and large area burns treatedwith conventional surgery. Epidermal stem cells are important for tissue engineering, butseverely burned patients remained extremely limited normal skin for stem cell therapy. Thenumber of not sufficient epidermal stem cells in normal skin only accounts for1%-10%ofskin base layer cells. This greatly limits the clinical application of epidermal stem cell tissueengineering technology. Is there any other method that can completely solve the shortage ofepidermal stem cells, produce them enough for transplant, and even realize "perfect woundhealing" eventually?
Cell dedifferentiation, a popular phenomenon founded recently, is a good way to produceabundant epidermal stem cells. Mature terminally differentiating epidermal cells can reverseto their precursor cells by dedifferentiation, that to say, Epidermal cells can reverse from "old"differentiated state to the not fully differentiated "young" state, even "naive" state with thecharacteristics of epidermal stem cells. These dedifferentiated yong epidermal cells can beused for the severe wound mentioned above. How can we actively induce differentiatedmature cells into lower differentiated immature state with a regenerative ability or directlyinto dedifferentiated epidermal stem cells with a strong regenerative ability?
The answer is obviously YES. It was reported that epidermal cell dedifferentiation hadbe induced by some specific factors. Therefore, it is important to establish a reliable andstable cell differentiation way to solve the stem cell shortage. Dedifferentiation isalternatively a moral and ethical way for disease therapy, with no genetic incompatibility ortissue rejection risk.
Several signaling pathways have been implicated in dedifferentiation of mature cellssuch as the Wnt/β-catenin, p38, extracellular signal-regulated kinase (ERK) and Janus kinase(JAK)/signal transducer and activator of transcription (STAT) signaling pathways. However,the pathway that induces differentiated epidermal cells to reverse into an immature state with a regenerative ability has not been reported. There is increasing evidence that Wnt signaling isnecessary for normal skin development, and a key effector in the Wnt signaling pathway isβ-catenin that is involved in maintenance of the progenitor cell population in skin. Studieshave also shown that elevated β-catenin levels lead to proliferation of epidermal stem cellsand induce trans-differentiation into hair follicle stem cells.
Based on our early epidermal stem cell research work, we continue to explore and try toestablish a stable skin stem cell culture system in the first part of the present study, which isimportant to further cell differentiation research. In the following part, the effect of β-cateninactivation on the characteristics of differentiated epidermal cells was investigated. First,β-catenin expression was induced by applying LiCl and a highly specific GSK-3β inhibitor.Then, the effects of β-catenin activation on morphological, phenotypic and growthcharacteristics of the dedifferentiated cells were observed. Finally, the ability ofdedifferentiated cells to regenerate a skin equivalent in vitro was investigated.
Methods
Differentiated human epidermal cells were isolated from epidermal sheets by differentialadhesion. Human foreskin specimens were digested at4℃with2mg/ml protease for10-12hand then the epidermis was isolated from the dermis. The isolated epidermis sheets were cutinto pieces, digested with0.25%trypsinase for20min at37℃and made into single-cellsuspensions. Then observe characteristics of epidermal stem cells under light and electronicmicroscopy, and immunohistochemical expression of epidermal stem cell series surfacemarkers.
For the second part of the experiment, differentiated human epidermal cells, isolatedfrom epidermal sheets by differential adhesion, were plated into6-well plates and divided intothree groups. LiCl and a highly specific GSK-3β inhibitor were added to the desired wells,and sodium chloride was added to the control without inhibitors according to the experimentalconditions. First, β-catenin expression was induced by applying LiCl and a highly specificGSK-3β inhibitor. Then, the effects of β-catenin activation on morphological, phenotypic andgrowth characteristics of the dedifferentiated cells were observed. Finally, the ability ofdedifferentiated cells to regenerate a skin equivalent in vitro was investigated.
Results
The isolated epidermal cells exhibited the characteristics of epidermal stem cells, smallround pearl shape with a large nuclear-cytoplasmic ratio and gradually changing into squareslab shape. In addition, less organelles were observed under electronic microscope. Twoweeks later the original cultured cells covered the bottle bottom. Cells cultured in growthpromoting factor DMEM/F12stick to the bottom24h later and covered the bottom in3-4d.The original generation epidermal stem cells immunohistochemically expressed epidermalstem cell series surface markers except for CK10.
Elevated expression of β-catenin in the nuclei of epidermal cells cultured with LiCl orGSK-3β inhibitor. β-catenin expression tested by Western Blot and measured by densitometricanalysis. There are striking differences in morphology between differentiated epidermal cellsand epidermal stem cells. The former are large flat-shaped cells with a smallnuclear-cytoplasmic ratio and the latter are small round shaped cells with a largenuclear-cytoplasmic ratio. These results demonstrated that the induced cells had morphologiccharacteristics of epidermal stem cells. The expression of CK10, CK19and β1integrin incultured epidermal cells in the presence of LiCl or GSK-3β inhibitor was studiedimmunohistochemically. LiCl or GSK-3β inhibitor significantly decreased the number andproportion of CK10positive cells. In contrast, CK19and β1integrin expression was enhancedby the addition of LiCl or GSK-3β inhibitor to the culture medium. Real-time PCR analysisrevealed that the induced cells were>4-6-fold enriched for both Oct4and Nanog comparedwith control. Cells in the control group grew dispersedly, but the cells treated with LiCl orGSK-3β inhibitor obviously formed colonies and the colonies gradually enlarged. However,there was no obvious difference in clonogenic capacity between LiCl or GSK-3βinhibitor-treated cells. In the induced groups, more cells were in the S and G2/M phase of thecell cycle compared with the control group. In the LiCl or GSK-3β inhibitor groups more cellswere in the proliferative phase. LiCl or GSK-3β inhibitor-induced cells have long-termgrowth potential. After11d, we found that differentiated epidermal cells could not form anepidermal monolayer, the induced epidermal cells and epidermal stem cells were capable ofregenerating a stratified epidermal layer on the dermal equivalent.
Conclusions
Epidermal stem cells can be effectively isolated by differential adhesion after early stageelectively digesting connections between dermis and epidermis. Low carbohydrate DMEM/F12(10%FBS) is a high-efficient medium for epidermal stem cells culture to keep theircharacteristics.
Differentiated epidermal cells regain the characteristics of epidermal stem cells byincreasing β-catenin expression. LiCl and GSK-3β inhibitor treatments resulted in anaccumulation of β-catenin in the nuclei of differentiated epidermal cells. The dedifferentiatedcells exhibited morphological, phenotypic and growth features of epidermal stem cells. Inaddition, dedifferentiated cells regenerated a skin equivalent similar to that of epidermal stemcells. These data suggest that abundant epidermal stem cells can be generated with an efficientdedifferentiation process by manipulating the expression of β-catenin. The Wnt/β-cateninsignaling pathway plays an important role in skin wound repair and regeneration
较大面积重度的全身烧创伤患者，通过皮肤移植等常规手术方法，几乎无一避免会出现创面瘢痕愈合的结局。虽然表皮干细胞对于严重创面修复的组织工程学具有重要帮助，但重度全身烧伤患者残存的正常皮肤很少，正常皮肤的表皮干细胞数量本身就很有限，只占正常表皮基底层的1%-10%，干细胞数量远达不到修复上述创面的要求，显然这会明显限制干细胞组织工程技术在临床上的广泛应用。是否有可以解决表皮干细胞短缺，获得足量的表皮干细胞将其移植到创面，最终可能实现创面的“完美修复”这样的方法呢？
去分化就是获得大量成体干细胞的途径之一，表皮细胞存在去分化现象。已分化成熟的终末分化表皮细胞通过去分化可以反向分成他们的父辈细胞，也就是说，表皮细胞可以从“年老的”分化状态返回到“年轻的”不完全分化、甚至具有表皮干细胞特征的幼稚状态的过程。而这些去分化来源的“年轻”细胞可用于上述创面治疗。我们如何主动地将已分化细胞在体外为诱导成为分化程度较低形式的细胞，甚至分化程度更低的再生皮肤能力更强的表皮干细胞呢？
答案是肯定的。有报道，某些特定因素可以诱导表皮细胞去分化。因此，建立可靠而稳定的去分化方法将从根本上解决上述疾病治疗面临的表皮干细胞数量短缺的严重问题。去分化方法是一符合道德、伦理规范的替代方案，没有遗传不相容和组织排斥风险。
成熟细胞去分化时涉及几条复杂的信号通路，如Wnt/β-连环蛋白、p38、细胞外信号调节激酶（ERK）和Janus激酶（JAK）/信号转导和转录激活因子（STAT）信号通路。但尚未有研究报告诱导分化表皮细胞退回到有再生能力不成熟状态的通路。越来越多的证据表明，Wnt信号转导对于皮肤的正常发育十分必要，Wnt信号通路的关键效应器是参与维持皮肤祖细胞群的β-连环蛋白。研究亦表明，β-连环蛋白水平升高会导致表皮干细胞增生并诱导细胞转分化为毛囊干细胞。
本研究第一部分是在前期表皮干细胞工作基础上，继续探讨并确立稳定的表皮干细胞培养体系，为深入去分化研究奠定基础。第二部分特别针对性探讨β-连环蛋白活化对于分化表皮细胞特性的影响。首先应用氯化锂（LiCl）和高度特异性GSK-3β抑制剂诱导β-连环蛋白表达，然后针对β-连环蛋白活化对于去分化细胞的形态、表型和生长特性的影响进行观察，最后对比去分化细胞体外再生表皮的能力。
二、方法
新鲜人包皮片前期处理后，用中性蛋白水解酶分离得到表皮，制成单细胞悬液，用差速贴壁法移去已分化表皮细胞，光镜和电镜下观察表皮干细胞的特点，并使用表皮干细胞标记物鉴定。利用差速贴壁法从表皮片中分离出人体表皮细胞接种于6孔板并分为3组，即对照组（无处理组），LiCl处理组和GSK-3β抑制剂处理组。应用LiCl和高度特异性GSK-3β抑制剂活化β-连环蛋白表达，针对β-连环蛋白活化对于去分化细胞的形态、表型和生长特性的影响观察，并对比细胞体外再生表皮的能力。
三、结果
差速贴壁法分离表皮得到的表皮干细胞具有干细胞的形态特点，光镜下细胞贴壁生长，由小圆珠状渐成方形的铺路石状。电镜下核大，细胞器少，为典型非成熟细胞。2周后原代细胞铺满瓶底。用含生长促进因子的DMEM/F12培养的表皮干细胞24h即可伸展贴壁和伸展，原代细胞3-4d即铺满瓶底。原代培养的表皮干细胞免疫组化显示表皮干细胞的系列表面标记物，不表达已分化表皮细胞的标记物CK10。
3组细胞中，免疫印迹和光动力学分析显示β-连环蛋白在LiCl组和GSK-3β抑制剂组表皮细胞核内的表达较未处理组显著增高。培养3、6d时，倒置相差显微镜下见两处理组细胞表现为表皮干细胞的典型变化。免疫组化分析表明两处理组CK10表达的数量和比例均显著下降，而表皮干细胞的标记物CK19和β1整合素的表达加强。与对照组相比，Oct4和Nanog基因在去分化的处理组细胞中高4-6倍。3d时两处理组已明显的集落形成，而对照组生长稀疏。流式细胞仪检测出的细胞周期数据表明两处理组中有较多细胞处于增殖期，且与对照组有显著差异。持续传代培养表明两处理组有更强的远期增殖潜能。培养11d后，对照组未成表皮单层，但处理组和表皮干细胞组在真皮替代物表面再生了复层表皮。
四、结论
采用中性蛋白酶选择性的水解真皮和表皮之间的细胞连接，再用差速贴壁法分离表皮干细胞是一种高效的表皮干细胞获取方法。含10%FBS低糖DMEM/F12是可以保持表皮干细胞去分化状态的良好培养基。
表皮细胞在分化后能够因β-连环蛋白的表达增加而重新恢复表皮干细胞的特征。LiCl和GSK-3β抑制剂处理可引起分化后表皮细胞胞核中的β-连环蛋白表达增加。去分化细胞表皮能表现出干细胞的形态、表型和生长特性。此外，去分化的细胞所再生的表皮与表皮干细胞所产生的类似。实验结果表明，通过调控β-连环蛋白的表达实现高效的去分化过程可产生丰富的表皮干细胞。Wnt/β-连环蛋白信号通路对皮肤创面修复与再生起着重要作用。
Background and Objectives
Scar outcome will inevitably appear in patients with severe and large area burns treatedwith conventional surgery. Epidermal stem cells are important for tissue engineering, butseverely burned patients remained extremely limited normal skin for stem cell therapy. Thenumber of not sufficient epidermal stem cells in normal skin only accounts for1%-10%ofskin base layer cells. This greatly limits the clinical application of epidermal stem cell tissueengineering technology. Is there any other method that can completely solve the shortage ofepidermal stem cells, produce them enough for transplant, and even realize "perfect woundhealing" eventually?
Cell dedifferentiation, a popular phenomenon founded recently, is a good way to produceabundant epidermal stem cells. Mature terminally differentiating epidermal cells can reverseto their precursor cells by dedifferentiation, that to say, Epidermal cells can reverse from "old"differentiated state to the not fully differentiated "young" state, even "naive" state with thecharacteristics of epidermal stem cells. These dedifferentiated yong epidermal cells can beused for the severe wound mentioned above. How can we actively induce differentiatedmature cells into lower differentiated immature state with a regenerative ability or directlyinto dedifferentiated epidermal stem cells with a strong regenerative ability?
The answer is obviously YES. It was reported that epidermal cell dedifferentiation hadbe induced by some specific factors. Therefore, it is important to establish a reliable andstable cell differentiation way to solve the stem cell shortage. Dedifferentiation isalternatively a moral and ethical way for disease therapy, with no genetic incompatibility ortissue rejection risk.
Several signaling pathways have been implicated in dedifferentiation of mature cellssuch as the Wnt/β-catenin, p38, extracellular signal-regulated kinase (ERK) and Janus kinase(JAK)/signal transducer and activator of transcription (STAT) signaling pathways. However,the pathway that induces differentiated epidermal cells to reverse into an immature state with a regenerative ability has not been reported. There is increasing evidence that Wnt signaling isnecessary for normal skin development, and a key effector in the Wnt signaling pathway isβ-catenin that is involved in maintenance of the progenitor cell population in skin. Studieshave also shown that elevated β-catenin levels lead to proliferation of epidermal stem cellsand induce trans-differentiation into hair follicle stem cells.
Based on our early epidermal stem cell research work, we continue to explore and try toestablish a stable skin stem cell culture system in the first part of the present study, which isimportant to further cell differentiation research. In the following part, the effect of β-cateninactivation on the characteristics of differentiated epidermal cells was investigated. First,β-catenin expression was induced by applying LiCl and a highly specific GSK-3β inhibitor.Then, the effects of β-catenin activation on morphological, phenotypic and growthcharacteristics of the dedifferentiated cells were observed. Finally, the ability ofdedifferentiated cells to regenerate a skin equivalent in vitro was investigated.
Methods
Differentiated human epidermal cells were isolated from epidermal sheets by differentialadhesion. Human foreskin specimens were digested at4℃with2mg/ml protease for10-12hand then the epidermis was isolated from the dermis. The isolated epidermis sheets were cutinto pieces, digested with0.25%trypsinase for20min at37℃and made into single-cellsuspensions. Then observe characteristics of epidermal stem cells under light and electronicmicroscopy, and immunohistochemical expression of epidermal stem cell series surfacemarkers.
For the second part of the experiment, differentiated human epidermal cells, isolatedfrom epidermal sheets by differential adhesion, were plated into6-well plates and divided intothree groups. LiCl and a highly specific GSK-3β inhibitor were added to the desired wells,and sodium chloride was added to the control without inhibitors according to the experimentalconditions. First, β-catenin expression was induced by applying LiCl and a highly specificGSK-3β inhibitor. Then, the effects of β-catenin activation on morphological, phenotypic andgrowth characteristics of the dedifferentiated cells were observed. Finally, the ability ofdedifferentiated cells to regenerate a skin equivalent in vitro was investigated.
Results
The isolated epidermal cells exhibited the characteristics of epidermal stem cells, smallround pearl shape with a large nuclear-cytoplasmic ratio and gradually changing into squareslab shape. In addition, less organelles were observed under electronic microscope. Twoweeks later the original cultured cells covered the bottle bottom. Cells cultured in growthpromoting factor DMEM/F12stick to the bottom24h later and covered the bottom in3-4d.The original generation epidermal stem cells immunohistochemically expressed epidermalstem cell series surface markers except for CK10.
Elevated expression of β-catenin in the nuclei of epidermal cells cultured with LiCl orGSK-3β inhibitor. β-catenin expression tested by Western Blot and measured by densitometricanalysis. There are striking differences in morphology between differentiated epidermal cellsand epidermal stem cells. The former are large flat-shaped cells with a smallnuclear-cytoplasmic ratio and the latter are small round shaped cells with a largenuclear-cytoplasmic ratio. These results demonstrated that the induced cells had morphologiccharacteristics of epidermal stem cells. The expression of CK10, CK19and β1integrin incultured epidermal cells in the presence of LiCl or GSK-3β inhibitor was studiedimmunohistochemically. LiCl or GSK-3β inhibitor significantly decreased the number andproportion of CK10positive cells. In contrast, CK19and β1integrin expression was enhancedby the addition of LiCl or GSK-3β inhibitor to the culture medium. Real-time PCR analysisrevealed that the induced cells were>4-6-fold enriched for both Oct4and Nanog comparedwith control. Cells in the control group grew dispersedly, but the cells treated with LiCl orGSK-3β inhibitor obviously formed colonies and the colonies gradually enlarged. However,there was no obvious difference in clonogenic capacity between LiCl or GSK-3βinhibitor-treated cells. In the induced groups, more cells were in the S and G2/M phase of thecell cycle compared with the control group. In the LiCl or GSK-3β inhibitor groups more cellswere in the proliferative phase. LiCl or GSK-3β inhibitor-induced cells have long-termgrowth potential. After11d, we found that differentiated epidermal cells could not form anepidermal monolayer, the induced epidermal cells and epidermal stem cells were capable ofregenerating a stratified epidermal layer on the dermal equivalent.
Conclusions
Epidermal stem cells can be effectively isolated by differential adhesion after early stageelectively digesting connections between dermis and epidermis. Low carbohydrate DMEM/F12(10%FBS) is a high-efficient medium for epidermal stem cells culture to keep theircharacteristics.
Differentiated epidermal cells regain the characteristics of epidermal stem cells byincreasing β-catenin expression. LiCl and GSK-3β inhibitor treatments resulted in anaccumulation of β-catenin in the nuclei of differentiated epidermal cells. The dedifferentiatedcells exhibited morphological, phenotypic and growth features of epidermal stem cells. Inaddition, dedifferentiated cells regenerated a skin equivalent similar to that of epidermal stemcells. These data suggest that abundant epidermal stem cells can be generated with an efficientdedifferentiation process by manipulating the expression of β-catenin. The Wnt/β-cateninsignaling pathway plays an important role in skin wound repair and regeneration
引文
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