本文選題：間充質(zhì)干細胞 + miRNA��； 參考：《第四軍醫(yī)大學(xué)》2016年碩士論文

【摘要】：【背景】近年來,由病毒、酒精、毒物或代謝等因素引起的肝臟衰竭呈逐年上升趨勢。特別是急性、亞急性及慢加急性肝功能衰竭,由于病因多,并發(fā)癥多和重要器官損傷多等特點,成為高發(fā)病率、高死亡率和治療非常棘手的疾病。肝移植是治療肝衰竭最有效的手段,但供肝的嚴重缺乏、治療費用昂貴及移植后的免疫排斥反應(yīng)等限制了它的廣泛應(yīng)用。人工肝支持系統(tǒng)可部分地清除體內(nèi)的毒性代謝產(chǎn)物,給患者自身肝臟再生創(chuàng)造條件。但由于其沒有肝臟的合成及代謝等功能,其治療療效有限。因此,急需開發(fā)具有一定肝臟功能的生物型人工肝支持系統(tǒng)。近年來,生物型人工肝支持系統(tǒng)逐漸成為治療急性肝衰竭最有效和最具潛力的治療方式。生物型人工肝支持系統(tǒng)主要由細胞成分,生物反應(yīng)器及輔助器材組成,其中細胞成分是生物型人工肝的核心問題。目前,種子細胞來源受到很多方面的限制,諸如自體肝細胞體外培養(yǎng)、增殖和保存技術(shù)有限,異種來源肝細胞存在免疫排斥效應(yīng)等。這些因素限制了生物型人工肝支持系統(tǒng)應(yīng)用于肝功能衰竭的治療。因此,我們需要尋找有功能的人源肝細胞,并可大規(guī)模生產(chǎn)。而近年來干細胞的發(fā)展為解決肝細胞來源提供了新的思路。我們前期研究通過對間充質(zhì)干細胞誘導(dǎo)分化得到的肝細胞樣細胞HLC與間充質(zhì)干細胞的micro RNA表達水平進行芯片分析,以及RT-PCR驗證比對等獲得一組表達量顯著上調(diào)的micro RNA組合:mi R-148a,mi R-424,mi R-1290,mi R-542-5p,mi R-1246和mi R-30a。在此基礎(chǔ)上,我們加入了肝臟特異性的mi R-122,作為一組micro RNA即7個mi RNA組合轉(zhuǎn)染進人臍帶間充質(zhì)干細胞內(nèi),成功實現(xiàn)了干細胞轉(zhuǎn)分化為肝細胞樣細胞(hepatocyte-like cells 7,HLC-7),并進行了一系列肝細胞樣細胞的功能驗證。我們證實這組由mi RNA組合誘導(dǎo)得到的細胞不僅表達肝特異基因,還具有LDL攝取,糖原沉積,尿素合成等一系列肝細胞功能。進一步,我們通過每組減少一種mi RNA獲得不同組合方式的方法繼續(xù)篩選對于人臍帶間充質(zhì)干細胞轉(zhuǎn)分化為肝細胞樣細胞的關(guān)鍵mi RNA或者組合。我們通過刪減mi R-30a和mi R-1290后的5種mi RNA(mi R-122,mi R-148a,mi R-424,mi R-542-5p和mi R-1246)轉(zhuǎn)染進臍帶MSC中,成功將其誘導(dǎo)分化為肝細胞樣細胞(HLC-5),能夠表達肝臟特異性基因ALB,AFP,HNF4A和TF等,PAS染色和LDL攝取試驗均為陽性,證實了誘導(dǎo)分化的成功。本研究將繼續(xù)采用n-1方法進一步刪減mi RNA組合,并驗證其體外的肝細胞功能。運用四氯化碳(Carbon tetrachloride,CCl4)建立裸鼠肝損傷和急性肝衰竭模型,并對肝損傷小鼠進行HLC移植治療,觀察對動物模型的修復(fù)作用�！灸康摹�1.明確mi RNA介導(dǎo)間充質(zhì)干細胞轉(zhuǎn)分化為肝細胞樣細胞的最優(yōu)組合;2.闡明HLCs在裸鼠肝損傷和肝衰竭中的修復(fù)作用�！痉椒ā�1.貼壁培養(yǎng)MSC,倒置顯微鏡觀察細胞形態(tài),流式細胞儀檢測表面標志,進行成脂和成骨誘導(dǎo)分化,明確MSC的純度和分化能力。2.篩檢mi RNA組合:驗證5種mi RNA(mi R-122,148a,424,542-5p和1246)的轉(zhuǎn)染效率以及誘導(dǎo)間充質(zhì)干細胞轉(zhuǎn)分化為肝細胞樣細胞的能力。在此基礎(chǔ)上,逐漸減少mi RNA的個數(shù),觀察轉(zhuǎn)染后的效應(yīng):主要通過RT-PCR檢測肝特異性基因表達水平,LDL攝取實驗、ICG攝取實驗、PAS糖原染色和尿素氮合成等試驗檢測HLC的肝細胞特異性功能。3.CCl4誘導(dǎo)裸鼠肝損傷,并隨機分為生理鹽水陰性對照組,HLC-7陽性對照和最優(yōu)組合誘導(dǎo)的HLC-N組,將生理鹽水和誘導(dǎo)細胞經(jīng)裸鼠尾靜脈移植(細胞數(shù)量1x106/只)。通過血清學(xué)檢測AST、ALT、ALB水平,HE染色和天狼星紅染色觀察造模損傷程度和細胞移植后的修復(fù)情況。4.高濃度CCl4誘導(dǎo)裸鼠急性肝衰竭,隨機分為生理鹽水陰性對照組,HLC-7陽性對照和最優(yōu)組合誘導(dǎo)的HLC-N組,并經(jīng)裸鼠尾靜脈進行移植。一周內(nèi)觀察裸鼠的生存情況�！窘Y(jié)果】1.貼壁培養(yǎng)的MSC呈類成纖維樣的梭形形態(tài),流式細胞儀檢測MSC表達99.8%的標志分子CD105,而造血干細胞標志CD34以及內(nèi)皮細胞標志CD31陽性率僅為0.2%,0.2%,表明MSC細胞純度較高。另外,茜素紅和油紅染色結(jié)果顯示MSC可以在誘導(dǎo)液作用下分化為骨細胞和脂肪細胞,具備多向分化的潛能。2.5種mi RNA轉(zhuǎn)染后的結(jié)果顯示:在轉(zhuǎn)染7天后,5種mi RNA均在轉(zhuǎn)染細胞中成功過表達;與NC組相比,HLC-5的肝特異性基因ALB,HNF4A,AFP等表達水平顯著升高,與HLC-7類似;而不表達其他非特異的PDX1,Ep CAM和CK7。肝特異性功能檢測結(jié)果顯示:LDL和ICG攝取實驗表明大部分的HLC-5可以攝取LDL,約40%可以攝取ICG;PAS染色結(jié)果提示大約60%的HLC-5都可以合成糖原;尿素合成實驗表明HLC-5具備合成尿素的能力,與對照組相比,具有統(tǒng)計學(xué)意義。3.4種mi RNA轉(zhuǎn)染后的結(jié)果顯示:轉(zhuǎn)染7天后,各組的細胞形態(tài)并無明顯改變;RT-PCR的結(jié)果顯示各組間ALB,HNF4A,AFP,CYP3A4和TF的m RNA水平與對照組相比并無明顯差異;LDL攝取實驗也表明4種mi RNA誘導(dǎo)的細胞不能成功攝取LDL。4.急性肝損傷模型結(jié)果顯示:CCl4處理后血清ALB明顯下降,AST和ALT升高,HE染色可見肝臟結(jié)構(gòu)破壞和炎細胞浸潤,提示急性肝損傷模型建立成功。與生理鹽水處理組相比,HLC-5和HLC-7移植后白蛋白水平升高,轉(zhuǎn)氨酶水平下降,血清結(jié)果明顯改善;HE染色提示肝臟組織結(jié)構(gòu)改善,炎癥減輕。5.急性肝衰竭模型結(jié)果表明:高濃度CCl4處理1天后,HE染色結(jié)果顯示肝臟組織結(jié)構(gòu)受損嚴重,炎性細胞浸潤。觀察一周內(nèi)的生存情況發(fā)現(xiàn),與生理鹽水對照組相比,HLC-5和HLC-7移植后可顯著改善裸鼠的生存時間。并且HLC-5和HLC-7兩組間并無明顯差異,說明在體內(nèi)HLC-5具有與HLC-7相似的功能。【結(jié)論】本研究表明,5種mi RNA(mi R-122,148a,424,542-5p和1246)是誘導(dǎo)臍帶間充質(zhì)干細胞轉(zhuǎn)分化為肝細胞樣細胞的最優(yōu)組合。誘導(dǎo)得到的HLC-5不僅在體外具備肝細胞的功能,在動物模型體內(nèi)也可發(fā)揮與HLC-7相似的損傷修復(fù)功能,并可顯著改善肝衰竭裸鼠的生存情況。這為肝細胞樣細胞在生物性人工肝的應(yīng)用提供了實驗基礎(chǔ)。而mi RNA調(diào)控轉(zhuǎn)分化的具體機制和HLC-5的細胞特點尚需要進一步探索。
[Abstract]:[background] in recent years, liver failure caused by virus, alcohol, poison or metabolism has been increasing year by year. Especially acute, subacute and slow and acute liver failure, due to many causes, many complications and many important organ damage, it has become a high incidence, high mortality and very difficult treatment. Liver transplantation is a serious disease. The most effective means for the treatment of liver failure, but the severe deficiency of the donor liver, the expensive treatment and the immune rejection after the transplantation limit its wide application. The artificial liver support system can partially remove the toxic metabolites in the body and create conditions for the patient's own liver regeneration. However, it has no function of liver synthesis and metabolism. In recent years, biological artificial liver support system has gradually become the most effective and potential treatment for acute liver failure. Biological artificial liver support system is mainly composed of cell components, bioreactors and auxiliary equipment groups. The cell composition is the core problem of the biotype artificial liver. At present, the source of seed cells is limited by many aspects, such as the culture of autologous liver cells in vitro, the limited proliferation and preservation techniques, and the immune rejection of xenogenic liver cells. These factors restrict the application of biological artificial liver support system to liver failure. Therefore, we need to find functional human derived hepatocytes and can be produced on a large scale. In recent years, the development of stem cells provides a new way of thinking for the solution of hepatocyte origin. We have studied the level of micro RNA expression of HLC and mesenchymal stem cells derived from mesenchymal stem cells. Chip analysis, and RT-PCR validation is a micro RNA combination that is significantly up - up of a set of expressions than peer to peer: Mi R-148a, MI R-424, MI R-1290, MI R-542-5p. The stem cells were transformed into hepatocyte like cells (hepatocyte-like cells 7, HLC-7), and the function of a series of hepatocyte like cells was verified. We confirmed that this group of cells induced by Mi RNA combination not only expressed liver specific genes, but also had a series of hepatocyte functions, such as LDL uptake, glycogen deposition, urea synthesis, and so on. We continue screening the key mi RNA or combination of human umbilical cord mesenchymal stem cells transdifferentiated into hepatocyte like cells by reducing one kind of MI RNA in each group. We transfect the 5 mi RNA of MI R-30a and MI R-12 90 (MI R-122) into umbilical cord It is successfully induced to differentiate into hepatocyte like cells (HLC-5), which can express liver specific genes ALB, AFP, HNF4A and TF. Both PAS staining and LDL uptake test are positive, which confirm the success of induced differentiation. This study will continue to use n-1 method to further reduce the MI RNA combination and verify the function of liver cells in vitro. Using carbon tetrachloride in vitro. (Carbon tetrachloride, CCl4) to establish a model of liver injury and acute liver failure in nude mice, and to treat the mice with liver injury by HLC transplantation and observe the repair effect of the animal model. [Objective] 1. to clarify the optimal combination of MI RNA mediated mesenchymal stem cells to turn into hepatocyte like cells; and 2. clarify HLCs in nude mice liver injury and liver failure. Repair effect. [Methods] 1. adherent culture MSC, inverted microscope to observe cell morphology, flow cytometry to detect surface markers, lipid and osteogenesis induced differentiation, clear MSC purity and differentiation ability.2. screening mi RNA combination: verify the transfection efficiency of 5 mi RNA (MI R-122148a, 424542-5p and 1246) and induce mesenchymal stem cells to transfer. The ability to differentiate into hepatocyte like cells. On this basis, the number of MI RNA was gradually reduced and the effect after transfection was observed: the detection of liver specific gene expression by RT-PCR, LDL uptake experiment, ICG uptake experiment, PAS glycogen staining and urea nitrogen synthesis test to detect the liver cell specific function.3.CCl4 of HLC to induce liver injury in nude mice And randomly divided into the normal saline negative control group, the HLC-7 positive control and the optimal combination induced HLC-N group, the physiological saline and the induced cells were transplanted in the tail vein of nude mice (the number of cells 1x106/ only). By serological detection of AST, ALT, ALB level, HE staining and Sirius red staining, the damage degree of the model and the restoration of the cells after the cell transplantation were observed. The high concentration of CCl4 induced acute liver failure in nude mice, randomly divided into the normal saline negative control group, the HLC-7 positive control and the optimal combination induced HLC-N group, and transplantable by the tail vein of nude mice. In a week, the survival of nude mice was observed. [results] the MSC of 1. adherent culture was like the spindle shape of the fibrinolytic type, and the flow cytometry was used to detect the MSC expression. 99.8% of the marker molecule CD105, and the hematopoietic stem cell marker CD34 and the endothelial cell marker CD31 positive rate is only 0.2%, 0.2%, indicating that the MSC cell purity is high. In addition, alizarin red and oil red staining results show that MSC can differentiate into bone and fat cells under the action of inducer, with the potential of multidirectional differentiation potential.2.5 species after MI RNA transfected. The results showed that 7 days after transfection, 5 kinds of MI RNA were overexpressed in transfected cells. Compared with group NC, the expression level of HLC-5 specific gene ALB, HNF4A, AFP was significantly higher, similar to HLC-7, but not other non specific PDX1, Ep CAM, and CK7. liver specific function detection results showed that most of the experimental results showed that the majority of them were found. 5 can take LDL, about 40% can absorb ICG; PAS staining results suggest that about 60% of HLC-5 can synthesize glycogen. The urea synthesis experiment shows that HLC-5 has the ability to synthesize urea. Compared with the control group, the results of.3.4 after MI RNA are statistically significant: the cell morphology of each group is not obviously changed after 7 days of transfection; RT-PCR The results showed that the m RNA levels of ALB, HNF4A, AFP, CYP3A4 and TF were not significantly different from those of the control group. LDL uptake experiments also showed that 4 mi RNA induced cells failed to successfully absorb the LDL.4. acute liver damage model. The acute liver injury model was successfully established. Compared with the saline treatment group, the level of albumin increased after HLC-5 and HLC-7 transplantation, the level of transaminase decreased and the serum results were obviously improved; HE staining suggested the improvement of liver tissue structure. The results of inflammation alleviating.5. acute liver failure model showed that high concentration CCl4 treatment was 1 days after HE staining results. The liver tissue structure was severely damaged and inflammatory cells infiltrated. Observation of survival within a week was found, compared with the saline control group, HLC-5 and HLC-7 could significantly improve the survival time of nude mice. There was no significant difference between the HLC-5 and the HLC-7 two groups, indicating that HLC-5 had a similar function to HLC-7 in the body. [Conclusion] this study The results show that 5 kinds of MI RNA (MI R-122148a, 424542-5p and 1246) are the best combinations to induce the differentiation of umbilical cord mesenchymal stem cells into hepatocyte like cells. The induced HLC-5 not only has the function of hepatocyte in vitro, but also can play a similar damage repair function with HLC-7 in the animal model, and can significantly improve the liver failure in nude mice. This provides an experimental basis for the application of hepatocyte like cells in biological artificial liver. The specific mechanism of MI RNA regulation of transdifferentiation and the cell characteristics of HLC-5 need to be further explored.
【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R575.3

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