Wnt5a抑制毛囊生長的體外及體內(nèi)實(shí)驗(yàn)研究
發(fā)布時(shí)間：2018-07-16 15:12
【摘要】：毛囊是一個(gè)復(fù)雜的皮膚附屬器官,它由上皮(毛母質(zhì)與多層同心圓狀結(jié)構(gòu))和真皮(毛乳頭和結(jié)締組織鞘)兩大部分組成,其中包含有20余種細(xì)胞,包括角質(zhì)形成細(xì)胞、黑色素細(xì)胞、Langerhans細(xì)胞、Merkel細(xì)胞、真皮鞘細(xì)胞和毛乳頭細(xì)胞,這些細(xì)胞在體內(nèi)經(jīng)過復(fù)雜的相互作用,共同參與了毛囊的發(fā)育、生長、分化與周期性的調(diào)節(jié)。毛囊依靠周期性循環(huán)來實(shí)現(xiàn)毛發(fā)的生長與更新,根據(jù)毛囊形態(tài)上的變化可將其分為三個(gè)階段:生長期(anagen)毛囊持續(xù)延長;退化期(catagen)毛乳頭開始上移,毛母質(zhì)細(xì)胞消失,毛囊逐漸縮短;靜止期(telogen)時(shí)毛乳頭到達(dá)真皮與皮下組織交界處,僅靠極小的上皮細(xì)胞索與毛囊相連。在毛囊生長的不同周期,一些活性蛋白、細(xì)胞因子及激素均可對(duì)毛囊周期或生長產(chǎn)生促進(jìn)或抑制作用。尋找能夠影響毛發(fā)生長的成分對(duì)闡明毛囊生長周期調(diào)控機(jī)制、發(fā)展治療脫發(fā)的有效手段具有重要意義。目前研究表明,毛囊的發(fā)生發(fā)育及周期維持受到多種信號(hào)途徑的調(diào)節(jié),如Wnt、Bmp、Shh等,其中經(jīng)典Wnt/β-catenin途徑日益引起人們的關(guān)注,該途徑被認(rèn)為是毛囊周期維持不可或缺的通路。目前在哺乳動(dòng)物中已發(fā)現(xiàn)19個(gè)Wnt蛋白家族成員,而且小鼠皮膚毛囊發(fā)育過程中同時(shí)存在多種Wnt的表達(dá),其中包括了經(jīng)典Wnts,也包括非經(jīng)典Wnts。但是,迄今為止對(duì)該家族兩大類Wnts在毛囊周期調(diào)控中的作用是否存在差異尚不明確。 Wnt5a (wingless-type MMTV integration site family, member 5A)作為Wnt家族非經(jīng)典Wnts的代表,在細(xì)胞的增殖、分化、遷移、運(yùn)動(dòng)、極性調(diào)節(jié)中有重要作用,其參與的信號(hào)網(wǎng)絡(luò)復(fù)雜交錯(cuò),除經(jīng)典Wnt途徑外還可激活多條非經(jīng)典Wnt信號(hào)途徑,如Wnt/Ca2+途徑、PCP途徑、Wnt/Ror2途徑等。最近研究發(fā)現(xiàn)非經(jīng)典Wnt5a途徑能通過促進(jìn)β-catenin降解,從而抑制經(jīng)典Wnt/β-catenin途徑的激活。為了更加清楚地了解Wnt5a在毛囊周期調(diào)控中的作用,本研究首先利用原位雜交、免疫組織化學(xué)、半定量RT-PCR和Western blot技術(shù),觀察Wnt5a在小鼠毛囊周期中的時(shí)空表達(dá)規(guī)律;其次在體外毛囊器官培養(yǎng)水平,采用腺病毒介導(dǎo)方式,檢測Wnt5a對(duì)毛囊生長的調(diào)控效應(yīng);然后采用拔毛同步化動(dòng)物模型,經(jīng)皮內(nèi)注射腺病毒,進(jìn)一步從在體水平驗(yàn)證Wnt5a對(duì)毛囊生長的影響,并運(yùn)用基因芯片檢測、定量RT-PCR、IHC等技術(shù),分析該效應(yīng)可能涉及的作用機(jī)制。本研究主要結(jié)果如下: 一、Wnt5a在小鼠毛囊周期中的表達(dá)規(guī)律 1.以地高辛標(biāo)記的Wnt5a RNA為探針,采用背皮whole-mount原位雜交技術(shù)觀察到:①生長期毛球部有較強(qiáng)的Wnt5a mRNA信號(hào),分布在matrix、IRS和DP,尤其是強(qiáng)增殖能力的matrix內(nèi)可觀察到大量的陽性細(xì)胞。大量Wnt5a由生長期毛囊細(xì)胞分泌,強(qiáng)烈提示它可能參與了對(duì)毛囊生長過程的調(diào)控。②進(jìn)入退化期后,發(fā)生凋亡的毛球部陽性信號(hào)逐漸減少。③靜止期毛囊中僅在DP見到少量Wnt5a mRNA表達(dá)。Wnt5a mRNA表達(dá)表現(xiàn)出顯著的周期性變化。 2.采用背皮組織的免疫組織化學(xué)方法觀察到:①Wnt5a蛋白在生長期毛囊中分布廣泛,除matrix、IRS、DP外,precortex細(xì)胞、ORS中也有分布,且表達(dá)量隨毛囊生長逐漸增多。Wnt5a蛋白分布范圍較mRNA更彌散,說明分泌Wnt5a的細(xì)胞和能接受Wnt5a信號(hào)的細(xì)胞可能不完全一致,提示W(wǎng)nt5a在毛囊中的作用途徑可能同時(shí)存在自分泌和旁分泌兩種方式。②到退化期,上皮索的表達(dá)逐漸減少。③進(jìn)入靜止期,少量Wnt5a蛋白的表達(dá)僅局限于bulge區(qū)、secondary hair germ和DP。 3.通過背皮組織半定量RT-PCR和Western blot技術(shù)觀察到,Wnt5a mRNA和蛋白的表達(dá)趨勢與原位雜交和IHC一致,均表現(xiàn)為生長期最豐富,退化期減弱,靜止期最低。 二、體外器官水平檢測Wnt5a對(duì)毛囊生長的作用 1.采用觸須組織的免疫組織化學(xué)方法,觀察到Wnt5a蛋白表達(dá)情況與背皮相似,說明這兩種毛囊類型中Wnt5a可能發(fā)揮相似調(diào)控作用。 2.利用腺病毒介導(dǎo)的方式,進(jìn)行觸須毛囊的體外器官培養(yǎng),觀察到:Wnt5a處理組毛囊的毛干伸出長度變短,提示W(wǎng)nt5a對(duì)毛囊生長有抑制作用。 三、動(dòng)物在體水平進(jìn)一步驗(yàn)證Wnt5a對(duì)毛囊生長的抑制作用 1.建立小鼠拔毛誘導(dǎo)同步化模型,經(jīng)皮內(nèi)注射腺病毒,觀察到Wnt5a組注射部位出現(xiàn)明顯抑毛區(qū),HE染色顯示該區(qū)毛囊為靜止期形態(tài),而周邊毛囊已經(jīng)進(jìn)入生長中期,提示W(wǎng)nt5a抑制了由于拔毛所誘導(dǎo)的毛囊生長,干擾了毛囊anagen的進(jìn)程。一段時(shí)間后,抑毛區(qū)會(huì)逐漸縮小直至消失,長出正常毛發(fā),說明單一的Wnt因素只能短暫抑制毛囊生長。 2.采用小鼠全基因組芯片檢測及定量RT-PCR,發(fā)現(xiàn)注射Wnt5a后β-catenin的水平顯著下調(diào),提示W(wǎng)nt5a的抑毛效應(yīng)可能是通過抑制經(jīng)典Wnt/β-catenin信號(hào)途徑而達(dá)到的。同時(shí)檢測到Rac2的表達(dá)顯著上調(diào),提示W(wǎng)nt5a可能激活了沿Rac2的PCP途徑信號(hào)鏈。 3.經(jīng)皮內(nèi)注射干擾β-catenin的腺病毒Ad-SimBC后,小鼠毛囊表型及HE染色改變類似于Wnt5a處理組,提示它們可能涉及到相似的分子機(jī)制,即抑制了經(jīng)典Wnt/β-catenin信號(hào)途徑。 4.對(duì)采用免疫組織化學(xué)染色技術(shù)檢測Wnt5a處理組和SimBC處理組,觀察到:經(jīng)典Wnt/β-catenin信號(hào)途徑的幾個(gè)分子β-catenin、Lef1、Dvl,增殖指標(biāo)Ki67和分化指標(biāo)AE15表達(dá)均下降,進(jìn)一步說明Wnt5a的抑毛效應(yīng)可能是通過抑制經(jīng)典Wnt/β-catenin途徑導(dǎo)致的。 總的來說,本課題通過一系列實(shí)驗(yàn)首先觀察了Wnt5a在毛囊周期中的表達(dá)規(guī)律,然后分別在體外器官培養(yǎng)水平和動(dòng)物在體水平,著重研究Wnt5a對(duì)毛囊生長的調(diào)控作用及可能的機(jī)制,旨在為深入研究不同Wnt信號(hào)在毛囊周期調(diào)控中的作用機(jī)理提供實(shí)驗(yàn)依據(jù);為毛發(fā)的生長調(diào)節(jié)、皮膚組織工程提供一定的理論基礎(chǔ)。
[Abstract]:The hair follicle is a complex skin accessory. It consists of two parts of the epithelium (the hair mother and the concentric circular structure) and the dermis (papillae and connective tissue sheath). It contains more than 20 kinds of cells, including keratinocytes, melanocytes, Langerhans cells, Merkel cells, dermal sheath cells and dermal papilla cells, and these cells. Through complex interaction in the body, it participates in the development, growth, differentiation and periodic regulation of hair follicles. Hair follicles rely on periodic circulation to realize hair growth and renewal. According to the morphological changes of the hair follicles, the hair follicles can be divided into three stages: the growth period (anagen) hair follicles continue to extend, and the degenerative period (catagen) of the hair nipple begins to move up. The hair mother cells disappear and the hair follicle gradually shortens; at telogen, the dermal papilla reaches the boundary between the dermis and the subcutaneous tissue and is connected to the hair follicle only by the tiny epithelial cells. In the different cycles of the follicle growth, some active proteins, cytokines and hormones can promote or inhibit the cycle or growth of the hair follicle. The composition of the hair growth is of great significance for clarifying the regulation mechanism of hair follicle growth cycle and developing the effective means of treating hair loss. At present, the research shows that the development and maintenance of hair follicles are regulated by various signal pathways, such as Wnt, Bmp, Shh and so on. Among them, the classical Wnt/ beta -catenin pathway is becoming more and more concerned. This approach is recognized. 19 Wnt protein family members have been found in mammals, and there are many Wnt expressions in the development of mouse hair follicles, including the classic Wnts, including the non classical Wnts., but so far the family of the family of the two major types of Wnts in the hair follicle cycle regulation It is not clear whether there is a difference in whether it exists.
Wnt5a (Wingless-type MMTV integration site family, member 5A), as the representative of the non classical Wnts of the Wnt family, plays an important role in cell proliferation, differentiation, migration, movement, and polarity regulation. The signal network involved is complex and interlaced. In addition to the classic Wnt pathway, many non classical Wnt signal pathways can be activated. Wnt/Ror2 pathway and so on. Recent studies have found that the non classical Wnt5a pathway can inhibit the activation of the classical Wnt/ beta -catenin pathway by promoting the degradation of beta -catenin. In order to understand the role of Wnt5a in the regulation of hair follicle cycle more clearly, this study first uses in situ hybridization, immunohistochemistry, semi quantitative RT-PCR and Western blot technology, to observe W. The temporal and spatial expression of nt5a in the cycle of mouse hair follicle; secondly in the culture level of hair follicle in vitro, using adenovirus mediated method to detect the regulation effect of Wnt5a on hair follicle growth, and then use the hair synchronization animal model and intradermal injection of adenovirus to further verify the effect of Wnt5a on the growth of hair follicles from the body level, and use the base. The mechanism of the effect may be analyzed by means of chip detection, quantitative RT-PCR, IHC and so on.
The expression of Wnt5a in the cycle of mouse hair follicle
1. with digoxin labeled Wnt5a RNA as a probe, the whole-mount in situ hybridization technique of dorsal skin was used to observe: (1) there was a strong Wnt5a mRNA signal in the growth period of the hair bulb, and a large number of positive cells were observed in matrix, IRS and DP, especially in the strong proliferative matrix. A large number of Wnt5a were secreted by the growth period hair follicle cells, strongly suggestive of it. It can participate in the regulation of the growth process of hair follicle. After entering the degenerative period, the positive signal of the apoptotic part of the hair bulb gradually decreases. (3) the expression of.Wnt5a mRNA expression of only a small amount of Wnt5a mRNA in the stillage hair follicle shows significant periodic changes.
2. the immunohistochemical method of the dorsal skin tissue was used to observe: (1) Wnt5a protein was widely distributed in the growth period hair follicles, except matrix, IRS, DP, precortex cells and ORS, and the expression of the protein was gradually increased with the growth of the follicle, and the distribution of.Wnt5a protein was more diffuse than mRNA, indicating the cells secreting Wnt5a and the cells that could receive Wnt5a signals. It may not be completely consistent, suggesting that the pathway of Wnt5a in hair follicles may exist in two ways of autocrine and paracrine. (2) the expression of the upper cord decreases gradually during the degenerative period. (3) the expression of the Wnt5a protein is limited to the bulge region, secondary hair germ and DP.
3. the expression trend of Wnt5a mRNA and protein was the same as in situ hybridization and IHC through the semi quantitative RT-PCR and Western blot techniques of the dorsal skin tissue. All of them showed that the growth period was the most abundant, the degenerate period weakened and the rest period was the lowest.
Two, in vitro organ level detection of Wnt5a on hair follicle growth.
1. the immunohistochemical staining of the tentacle tissue was used to observe the expression of Wnt5a protein as similar to the dorsal skin, indicating that Wnt5a may play a similar role in the two hair follicle types.
2. the organ culture of the tentacle hair follicle in vitro was carried out by adenovirus mediated method. It was observed that the hair length of hair follicles in the Wnt5a treatment group shortened, suggesting that Wnt5a could inhibit the growth of hair follicles.
Three, animal in vivo level further verified the inhibitory effect of Wnt5a on hair follicle growth.
1. the model of inducing hair induction synchronizing in mice was established. After intradermal injection of adenovirus, it was observed that the injection site of Wnt5a group had obvious hair suppression area. HE staining showed that the hair follicle in this area was stationary phase, and the peripheral hair follicle had entered the middle growth period, suggesting that Wnt5a inhibited the growth of hair follicle induced by plucking and interfered with the process of hair follicle anagen. After the time, the hair suppression area will gradually shrink to disappear and grow normal hair, which indicates that a single Wnt factor can only temporarily inhibit hair follicle growth.
2. the whole genome chip detection and quantitative RT-PCR were used to detect the level of beta -catenin after the injection of Wnt5a, suggesting that the inhibitory effect of Wnt5a might be achieved by inhibiting the classical Wnt/ beta -catenin signal pathway. Meanwhile, the expression of Rac2 was significantly up-regulated, suggesting that Wnt5a may activate the PCP pathway chain along Rac2.
3. after intradermal injection of adenovirus Ad-SimBC interfering with beta -catenin, the phenotype of hair follicles and HE staining changes in mice are similar to those in the Wnt5a treatment group, suggesting that they may involve a similar molecular mechanism, that is, the inhibition of the classical Wnt/ beta -catenin signal pathway.
4. the Wnt5a treatment group and SimBC treatment group were detected by immunohistochemical staining. The expression of several molecules beta -catenin, Lef1, Dvl, proliferation index Ki67 and differentiation index of the classical Wnt/ beta -catenin signal pathway were decreased, which further indicated that the inhibition effect of Wnt5a was probably caused by the inhibition of the classic Wnt/ beta -catenin pathway.
In general, this topic first observed the expression of Wnt5a in the hair follicle cycle through a series of experiments, then respectively in the level of organ culture in vitro and in the body level of animals, focusing on the regulatory role of Wnt5a on hair follicle growth and possible mechanisms, aiming at studying the mechanism of different Wnt signals in the regulation of hair follicle cycle. It provides experimental basis and provides a theoretical basis for skin growth engineering and skin tissue engineering.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R751
[Abstract]:The hair follicle is a complex skin accessory. It consists of two parts of the epithelium (the hair mother and the concentric circular structure) and the dermis (papillae and connective tissue sheath). It contains more than 20 kinds of cells, including keratinocytes, melanocytes, Langerhans cells, Merkel cells, dermal sheath cells and dermal papilla cells, and these cells. Through complex interaction in the body, it participates in the development, growth, differentiation and periodic regulation of hair follicles. Hair follicles rely on periodic circulation to realize hair growth and renewal. According to the morphological changes of the hair follicles, the hair follicles can be divided into three stages: the growth period (anagen) hair follicles continue to extend, and the degenerative period (catagen) of the hair nipple begins to move up. The hair mother cells disappear and the hair follicle gradually shortens; at telogen, the dermal papilla reaches the boundary between the dermis and the subcutaneous tissue and is connected to the hair follicle only by the tiny epithelial cells. In the different cycles of the follicle growth, some active proteins, cytokines and hormones can promote or inhibit the cycle or growth of the hair follicle. The composition of the hair growth is of great significance for clarifying the regulation mechanism of hair follicle growth cycle and developing the effective means of treating hair loss. At present, the research shows that the development and maintenance of hair follicles are regulated by various signal pathways, such as Wnt, Bmp, Shh and so on. Among them, the classical Wnt/ beta -catenin pathway is becoming more and more concerned. This approach is recognized. 19 Wnt protein family members have been found in mammals, and there are many Wnt expressions in the development of mouse hair follicles, including the classic Wnts, including the non classical Wnts., but so far the family of the family of the two major types of Wnts in the hair follicle cycle regulation It is not clear whether there is a difference in whether it exists.
Wnt5a (Wingless-type MMTV integration site family, member 5A), as the representative of the non classical Wnts of the Wnt family, plays an important role in cell proliferation, differentiation, migration, movement, and polarity regulation. The signal network involved is complex and interlaced. In addition to the classic Wnt pathway, many non classical Wnt signal pathways can be activated. Wnt/Ror2 pathway and so on. Recent studies have found that the non classical Wnt5a pathway can inhibit the activation of the classical Wnt/ beta -catenin pathway by promoting the degradation of beta -catenin. In order to understand the role of Wnt5a in the regulation of hair follicle cycle more clearly, this study first uses in situ hybridization, immunohistochemistry, semi quantitative RT-PCR and Western blot technology, to observe W. The temporal and spatial expression of nt5a in the cycle of mouse hair follicle; secondly in the culture level of hair follicle in vitro, using adenovirus mediated method to detect the regulation effect of Wnt5a on hair follicle growth, and then use the hair synchronization animal model and intradermal injection of adenovirus to further verify the effect of Wnt5a on the growth of hair follicles from the body level, and use the base. The mechanism of the effect may be analyzed by means of chip detection, quantitative RT-PCR, IHC and so on.
The expression of Wnt5a in the cycle of mouse hair follicle
1. with digoxin labeled Wnt5a RNA as a probe, the whole-mount in situ hybridization technique of dorsal skin was used to observe: (1) there was a strong Wnt5a mRNA signal in the growth period of the hair bulb, and a large number of positive cells were observed in matrix, IRS and DP, especially in the strong proliferative matrix. A large number of Wnt5a were secreted by the growth period hair follicle cells, strongly suggestive of it. It can participate in the regulation of the growth process of hair follicle. After entering the degenerative period, the positive signal of the apoptotic part of the hair bulb gradually decreases. (3) the expression of.Wnt5a mRNA expression of only a small amount of Wnt5a mRNA in the stillage hair follicle shows significant periodic changes.
2. the immunohistochemical method of the dorsal skin tissue was used to observe: (1) Wnt5a protein was widely distributed in the growth period hair follicles, except matrix, IRS, DP, precortex cells and ORS, and the expression of the protein was gradually increased with the growth of the follicle, and the distribution of.Wnt5a protein was more diffuse than mRNA, indicating the cells secreting Wnt5a and the cells that could receive Wnt5a signals. It may not be completely consistent, suggesting that the pathway of Wnt5a in hair follicles may exist in two ways of autocrine and paracrine. (2) the expression of the upper cord decreases gradually during the degenerative period. (3) the expression of the Wnt5a protein is limited to the bulge region, secondary hair germ and DP.
3. the expression trend of Wnt5a mRNA and protein was the same as in situ hybridization and IHC through the semi quantitative RT-PCR and Western blot techniques of the dorsal skin tissue. All of them showed that the growth period was the most abundant, the degenerate period weakened and the rest period was the lowest.
Two, in vitro organ level detection of Wnt5a on hair follicle growth.
1. the immunohistochemical staining of the tentacle tissue was used to observe the expression of Wnt5a protein as similar to the dorsal skin, indicating that Wnt5a may play a similar role in the two hair follicle types.
2. the organ culture of the tentacle hair follicle in vitro was carried out by adenovirus mediated method. It was observed that the hair length of hair follicles in the Wnt5a treatment group shortened, suggesting that Wnt5a could inhibit the growth of hair follicles.
Three, animal in vivo level further verified the inhibitory effect of Wnt5a on hair follicle growth.
1. the model of inducing hair induction synchronizing in mice was established. After intradermal injection of adenovirus, it was observed that the injection site of Wnt5a group had obvious hair suppression area. HE staining showed that the hair follicle in this area was stationary phase, and the peripheral hair follicle had entered the middle growth period, suggesting that Wnt5a inhibited the growth of hair follicle induced by plucking and interfered with the process of hair follicle anagen. After the time, the hair suppression area will gradually shrink to disappear and grow normal hair, which indicates that a single Wnt factor can only temporarily inhibit hair follicle growth.
2. the whole genome chip detection and quantitative RT-PCR were used to detect the level of beta -catenin after the injection of Wnt5a, suggesting that the inhibitory effect of Wnt5a might be achieved by inhibiting the classical Wnt/ beta -catenin signal pathway. Meanwhile, the expression of Rac2 was significantly up-regulated, suggesting that Wnt5a may activate the PCP pathway chain along Rac2.
3. after intradermal injection of adenovirus Ad-SimBC interfering with beta -catenin, the phenotype of hair follicles and HE staining changes in mice are similar to those in the Wnt5a treatment group, suggesting that they may involve a similar molecular mechanism, that is, the inhibition of the classical Wnt/ beta -catenin signal pathway.
4. the Wnt5a treatment group and SimBC treatment group were detected by immunohistochemical staining. The expression of several molecules beta -catenin, Lef1, Dvl, proliferation index Ki67 and differentiation index of the classical Wnt/ beta -catenin signal pathway were decreased, which further indicated that the inhibition effect of Wnt5a was probably caused by the inhibition of the classic Wnt/ beta -catenin pathway.
In general, this topic first observed the expression of Wnt5a in the hair follicle cycle through a series of experiments, then respectively in the level of organ culture in vitro and in the body level of animals, focusing on the regulatory role of Wnt5a on hair follicle growth and possible mechanisms, aiming at studying the mechanism of different Wnt signals in the regulation of hair follicle cycle. It provides experimental basis and provides a theoretical basis for skin growth engineering and skin tissue engineering.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R751
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