本文選題：間充質(zhì)干細(xì)胞 + 成脂誘導(dǎo)分化��； 參考：《北京協(xié)和醫(yī)學(xué)院》2016年博士論文

【摘要】：背景：人骨髓間充質(zhì)干細(xì)胞(bone marrow mesenchymal stem cells, BM-MSCs)是一類(lèi)具有自我更新和多向分化潛能的成體干細(xì)胞,是構(gòu)成骨髓微環(huán)境的主要細(xì)胞成分之一,在調(diào)控微環(huán)境中干細(xì)胞穩(wěn)態(tài)和維持干細(xì)胞的功能中發(fā)揮重要作用。BM-MSCs分化能力的異常,通過(guò)改變其正常BM-MSCs的免疫調(diào)節(jié)能力和造血支持功能,從而在各種血液性疾病和相應(yīng)免疫性疾病中發(fā)揮重要作用。Notch信號(hào)通路(Notch signaling pathway)是一條經(jīng)典的跨膜信號(hào)通路,通過(guò)受體與配體結(jié)合,作用于PI3K/Akt通路在調(diào)控細(xì)胞生長(zhǎng)、發(fā)育和凋亡中發(fā)揮重要作用,而PI3K/Akt/mTOR通路作為自噬(autophagy)的調(diào)控信號(hào),是自噬發(fā)生中重要的靶點(diǎn)。此外,研究認(rèn)為自噬的發(fā)生在細(xì)胞生長(zhǎng)和分化中起著重要作用。因此,以PI3K/Akt/mTOR信號(hào)通路為切入點(diǎn),探討Notch信號(hào)與自噬發(fā)生在BM-MSCs成脂誘導(dǎo)分化過(guò)程中的作用,為闡述臨床疾病中MSCs的異常分化提供理論基礎(chǔ)。目的：研究Notch信號(hào)通路和自噬發(fā)生在正常骨髓間充質(zhì)干細(xì)胞成脂誘導(dǎo)分化過(guò)程中的表達(dá)變化情況,并進(jìn)一步闡明Notch信號(hào)和自噬發(fā)生在骨髓間充質(zhì)干細(xì)胞成脂誘導(dǎo)分化中發(fā)揮作用可能涉及的機(jī)制,為研究間充質(zhì)干細(xì)胞的成脂分化提供實(shí)驗(yàn)支持和理論依據(jù)。方法：(1)采用貼壁、傳代培養(yǎng)方法獲得正常人骨髓組織中BM-MSCs;通過(guò)成脂誘導(dǎo)分化和成骨誘導(dǎo)分化檢測(cè)BM-MSCs多向分化潛能；流式細(xì)胞儀檢測(cè)BM-MSCs免疫表型。 (2)應(yīng)用Real-time PCR和Western blot檢測(cè)BM-MSCs成脂誘導(dǎo)分化過(guò)程中Notch信號(hào)和自噬水平的表達(dá)變化情況。(3)篩選不同濃度Notch信號(hào)抑制劑DAPT(0μM、2.5 μM、5μM和10M)對(duì)BM-MSCs中Notch信號(hào)表達(dá)抑制情況。(4)在BM-MSCs成脂誘導(dǎo)分化過(guò)程中,加用Notch信號(hào)抑制劑DAPT(5μM),通過(guò)油紅O染色和Real-time PCR檢測(cè)成脂相關(guān)基因PPARy和C/EBPa mRNA表達(dá)變化,評(píng)價(jià)抑制Notch信號(hào)對(duì)BM-MSCs成脂分化能力的影響。(5)應(yīng)用自噬抑制劑3-MA(5 mM)或氯喹(20μM)抑制BM-MSCs分化早期自噬發(fā)生,同時(shí)單用或聯(lián)合應(yīng)用DAPT,驗(yàn)證自噬發(fā)生對(duì)DAPT促BM-MSCs成脂分化能力產(chǎn)生影響。(6)采用Western blot檢測(cè)BM-MSCs成脂分化過(guò)程中PI3K/Akt/mTOR信號(hào)通路中相應(yīng)蛋白表達(dá)變化情況。(7)應(yīng)用MDC染色、透射電鏡和Western blot聯(lián)合檢測(cè),探討Notch信號(hào)抑制劑DAPT是否通過(guò)PI3K/Akt/mTOR信號(hào)對(duì)BM-MSCs自噬發(fā)生產(chǎn)生影響。(8)Western blot方法和共聚焦染色方法檢測(cè)自噬抑制劑3-MA (5mM)或氯喹(20 μM)對(duì)DAPT促BM-MSCs自噬發(fā)生的逆轉(zhuǎn)作用。結(jié)果： (1)成功分離培養(yǎng)獲得高純度的人BM-MSCs,正常BM-MSCs細(xì)胞形態(tài)呈長(zhǎng)梭形或多角形,旋渦狀生長(zhǎng)；具有成脂誘導(dǎo)分化和成骨誘導(dǎo)分化能力；流式細(xì)胞儀檢測(cè)BM-MSCs免疫表型,其高表達(dá)CD44、CD73、CD90、CD105和CD166,不表達(dá)CD14、CD19、CD34、CD45和HLA-DR。(2)BM-MSCs在成脂誘導(dǎo)培養(yǎng)體系中誘導(dǎo)分化14天,Notch受體NOTCH1、NOTCH2和NOTCH3 mRNA明顯降低(P0.05),NOTCH4 mRNA有下降趨勢(shì),但無(wú)統(tǒng)計(jì)學(xué)意義(P0.05)；Notch配體DLL1、DLL3、DLL4、DLK1和DLK2 mRNA表達(dá)明顯下降(P0.05),Jagged1和Jagged2 mRNA無(wú)明顯變化(P0.05)；Notch信號(hào)依賴(lài)的轉(zhuǎn)錄因子HEY1下降明顯(P0.05),HES1和HEY2無(wú)明顯變化(P0.05)。(3)在BM-MSCs成脂誘導(dǎo)分化早期,自噬相關(guān)蛋白LC-3和Beclin 1表達(dá)量顯著升高,表明在分化早期自噬水平增加,隨著B(niǎo)M-MSCs成脂誘導(dǎo)時(shí)間延長(zhǎng),自噬水平逐漸降低。(4)5 μMDAPT能夠有效抑制BM-MSCs中Notch信號(hào)的表達(dá)。(5)BM-MSCs成脂誘導(dǎo)分化過(guò)程中,單獨(dú)加入Notch信號(hào)抑制劑DAPT(5 μM),或聯(lián)合應(yīng)用自噬抑制劑3-MA(5 mM)或氯喹(20μM),通過(guò)油紅O染色和成脂相關(guān)基因PPARγ和C/EBPa mRNA檢測(cè)證實(shí),DAPT可能通過(guò)激活自噬發(fā)生而促進(jìn)BM-MSCs成脂誘導(dǎo)分化。(6)PTEN-PI3K/Akt/mTOR通路在BM-MSCs成脂誘導(dǎo)分化過(guò)程中伴隨成脂誘導(dǎo)進(jìn)程發(fā)生時(shí)間相關(guān)性改變。 (7)Notch抑制劑DAPT通過(guò)作用于PTEN-PI3K/Akt/mTOR信號(hào)通路誘導(dǎo)BM-MSCs自噬的發(fā)生。結(jié)論：BM-MSCs成脂誘導(dǎo)分化過(guò)程中Notch信號(hào)表達(dá)降低,而細(xì)胞自噬水平在BM-MSCs成脂誘導(dǎo)分化早期激活；Notch信號(hào)抑制劑DAPT能夠促進(jìn)BM-MSCs成脂誘導(dǎo)分化,而抑制分化早期自噬的發(fā)生能夠逆轉(zhuǎn)DAPT的促成脂作用；DAPT抑制Notch信號(hào)通過(guò)作用于PTEN-PI3K/Akt/mTOR通路激活BM-MSCs自噬發(fā)生從而促進(jìn)其成脂分化。背景：間充質(zhì)干細(xì)胞(mesenchmal stem cells, MSCs)因其具有自我更新和多向分化潛能而被廣泛應(yīng)用于組織損傷修復(fù)和再生醫(yī)學(xué)臨床應(yīng)用中。MSCs來(lái)源十分廣泛,可從骨髓、脂肪、臍帶和胎盤(pán)等眾多組織中分離獲得,其中人臍帶間充質(zhì)干細(xì)胞(human umbilical cord mesenchymal stem cells, hUC-MSCs)因其具有取材容易,體外擴(kuò)增快且不涉及倫理問(wèn)題等特點(diǎn)受到更多關(guān)注。成脂分化和成骨分化作為MSCs主要的分化方向,對(duì)于探索MSCs功能試驗(yàn)和臨床研究具有重要意義。半乳糖凝集素(Galectins)作為p-半乳糖苷結(jié)合凝集素家族中的一員在調(diào)控細(xì)胞免疫、抗原識(shí)別、神經(jīng)發(fā)生和血管生成中具有重要作用,最新研究認(rèn)為家族中某些亞型參與了細(xì)胞分化和脂肪細(xì)胞生成,但是目前對(duì)于Galectins在hUC-MSCs成脂分化和成骨分化中的作用尚不明確。目的：檢測(cè)Galectins家族成員在hUC-MSCs成脂分化和成骨分化過(guò)程中的表達(dá)變化情況,為進(jìn)一步研究hUC-MSCs分化功能提供一定的理論基礎(chǔ)。方法： (1)分離提純?nèi)四殠чg充質(zhì)干細(xì)胞,通過(guò)流式細(xì)胞儀檢測(cè)其間充質(zhì)干細(xì)胞免疫表型,油紅O染色、Von Kossa染色和茜素紅染色觀察其成脂分化和成骨分化能力,鑒定分離的hUC-MSCs;(2)RT-PCR半定量檢測(cè)hUC-MSCs內(nèi)Galectins各成員(Gal-1、Gal-2、Gal-3、Gal-4、Gal-7、Gal-8、Gal-9、Gal-10、Gal-12、Gal-13和Gal-14)表達(dá)變化情況,篩選出其高表達(dá)亞型；(3)Real-time PCR檢測(cè)hUC-MSCs成脂分化和成骨分化過(guò)程中不同時(shí)間段(第0天、1天、3天、7天、14天和21天)Gal-1、Gal-3、Gal-8和Gal-9 mRNA表達(dá)變化情況； (4)收集hUC-MSCs成脂分化和成骨分化過(guò)程中不同時(shí)間段細(xì)胞培養(yǎng)上清,通過(guò)ELISA檢測(cè)Gal-1和Gal-9分泌蛋白表達(dá)。結(jié)果：(1)所分離hUC-MSCs高表達(dá)D29、CD73、CD90、CD105、CD44、CD166和HLA-ABC,不表達(dá)CD14、CD31、CD45、CD133和HLA-DR,且在體外誘導(dǎo)條件下,具有向脂肪細(xì)胞和成骨細(xì)胞成分化能力。(2)hUC-MSCs細(xì)胞表達(dá)Galectins家族中Gal-1、Gal-3、Gal-7、Gal-8、Gal-9、Gal-10、Gal-12和Gal-13亞型,其中Gal-1、Gal-3、Gal-8和Gal-9 mRNA表達(dá)量較高。(3)Gal-1 mRNA和Gal-9 mRNA在hUC-MSCs成脂分化和成骨分化過(guò)程中隨誘導(dǎo)時(shí)間進(jìn)程逐漸降低；而Gal-3mRNA和Gal-8 mRNA在hUC-MSCs成脂分化和成骨分化過(guò)程中隨誘導(dǎo)時(shí)間進(jìn)程逐漸升高。 (4)ELISA檢測(cè)提示Gal-1和Gal-9可能通過(guò)外分泌作用在hUC-MSCs成脂分化和成骨分化過(guò)程中發(fā)揮作用。結(jié)論：Galecins (Gal-1、Gal-3、Gal-8和Gal-9)在hUC-MSCs成脂分化和成骨分化過(guò)程中表達(dá)變化明顯,其中Gal-1和Gal-9可能通過(guò)外分泌發(fā)揮作用,為進(jìn)一步研究Galectins在hUC-MSCs分化中的作用提供了理論基礎(chǔ)。
[Abstract]:Background: human bone marrow mesenchymal stem cells (bone marrow mesenchymal stem cells, BM-MSCs) are adult stem cells with self renewal and pluripotent differentiation potential. It is one of the main cell components that constitute the microenvironment of bone marrow. It plays an important role in regulating the homeostasis of stem cells and maintaining the function of stem cells in the micro environment and plays an important role in the differentiation of.BM-MSCs. Abnormality of ability, by changing the immune regulation ability and hematopoietic support function of normal BM-MSCs, plays an important role in various blood diseases and corresponding immune diseases. The.Notch signaling pathway (Notch signaling pathway) is a classic transmembrane signaling pathway, through the binding of receptor to ligand, and the role of PI3K/Akt pathway in modulation. The cell growth, development and apoptosis play an important role, and the PI3K/Akt/mTOR pathway is an important target for autophagy (autophagy). In addition, it is considered that the occurrence of autophagy plays an important role in cell growth and differentiation. Therefore, the PI3K/Akt/mTOR signal pathway is used as the breakthrough point to explore the Notch signal and self. The role of phagocytosis in BM-MSCs lipid induced differentiation provides a theoretical basis for explaining the abnormal differentiation of MSCs in clinical diseases. Objective: To study the changes in the expression of Notch signaling pathway and autophagy during the induced differentiation of normal bone marrow mesenchymal stem cells (MSCs), and to further elucidate the occurrence of Notch signals and autophagy in bone. The mechanism of action may be involved in the lipid induced differentiation of MSCs to provide experimental support and theoretical basis for the study of lipid differentiation of mesenchymal stem cells. Methods: (1) BM-MSCs in normal human bone marrow tissues was obtained by adherence and passage culture, and BM-MSCs multidirection was detected by lipid induced differentiation and osteogenic differentiation. Differentiation potential; flow cytometry was used to detect BM-MSCs immunophenotype. (2) the expression of Notch signal and autophagy level in BM-MSCs induced lipid induced differentiation was detected by Real-time PCR and Western blot. (3) the inhibition of DAPT (0 mu M, 2.5 mu M, 5 micronM and 4) on the expression inhibition of Notch signal inhibitors. (4) In the process of BM-MSCs lipid induced differentiation, Notch signal inhibitor DAPT (5 mu M) was used to detect the expression changes of lipid related genes PPARy and C/EBPa mRNA through oil red O staining and Real-time PCR, and the effect of inhibiting Notch signal on lipid differentiation ability of BM-MSCs was evaluated. (5) the application of autophagic inhibitor (5) or chloroquine (20 mu) to inhibit the early differentiation Autophagy occurs at the same time, at the same time using single or combined use of DAPT to verify the effect of autophagy on the ability of DAPT to promote BM-MSCs differentiation. (6) Western blot was used to detect the changes in the expression of corresponding proteins in the PI3K/Akt/mTOR signaling pathway of BM-MSCs in the process of lipid differentiation. (7) MDC staining, transmission electron microscopy and Western blot combined detection, and Notch on Notch Whether the signal inhibitor DAPT affects the autophagy of BM-MSCs through the PI3K/Akt/mTOR signal. (8) Western blot method and confocal staining method are used to detect the reversal effect of autophagy inhibitor 3-MA (5mM) or chloroquine (20 mu M) on the autophagy of DAPT BM-MSCs. Results: (1) high purity human BM-MSCs, normal BM-MSCs thin is obtained. Cell morphology was long spindle shaped or polygonal, vortexed, with lipid induced differentiation and osteogenic differentiation, and BM-MSCs immunophenotype was detected by flow cytometry, which expressed high expression of CD44, CD73, CD90, CD105 and CD166, and did not express CD14, CD19, CD34, CD45 and HLA-DR. (2) induction and differentiation for 14 days in the lipid induced culture system. H1, NOTCH2 and NOTCH3 mRNA decreased significantly (P0.05), and NOTCH4 mRNA declined, but there was no statistical significance (P0.05). (P0.05) (3) the expression of autophagy related protein LC-3 and Beclin 1 increased significantly at the early stage of BM-MSCs induced differentiation, indicating that the autophagy level increased at the early stage of differentiation, and the autophagy level gradually decreased with the prolongation of BM-MSCs induction time. (4) 5 micron MDAPT could effectively inhibit the expression of Notch signal in BM-MSCs. (5) BM-MSCs induced differentiation process. Notch signal inhibitor DAPT (5 mu M), or combined use of autophagy inhibitor 3-MA (5 mM) or chloroquine (20 micron M), was confirmed by oil red O staining and lipid related genes PPAR y and C/EBPa mRNA. DAPT may promote lipoid induced differentiation by activating autophagy. (6) the pathway is induced by lipid induced differentiation. (7) Notch inhibitor DAPT induced BM-MSCs autophagy by acting on the PTEN-PI3K/Akt/mTOR signaling pathway. Conclusion: the expression of Notch signal in BM-MSCs induced differentiation is reduced, and the level of autophagy is activated at the early stage of BM-MSCs induced differentiation; Notch letter Inhibitor DAPT can promote BM-MSCs induced differentiation, and inhibition of autophagy at early differentiation can reverse the effect of DAPT on lipid action; DAPT inhibits Notch signal to activate BM-MSCs autophagy by activating the PTEN-PI3K/Akt/mTOR pathway to promote its lipid differentiation. Background: mesenchymal stem cells (Mesenchmal stem cells, MSCs) .MSCs is widely used in the clinical application of tissue injury repair and regenerative medicine, which is widely used in tissue injury repair and regenerative medicine. It can be isolated from many tissues such as bone marrow, fat, umbilical cord and placenta. The human umbilical cord mesenchymal stem cells (human umbilical cord mesenchymal stem cells, hUC-MSCs) have a wide range of sources. More attention has been paid to the characteristics of easy extraction, rapid expansion in vitro and without ethical problems. Lipid differentiation and osteogenic differentiation as the main differentiation direction of MSCs is of great significance for exploring MSCs functional tests and clinical studies. As a member of the family of p- galactoside binding lectin, a member of galactoagglutinin (Galectins) is well regulated. Cellular immunity, antigen recognition, neurogenesis and angiogenesis are important. Recent studies suggest that some subtypes of the family have been involved in cell differentiation and adipocyte formation, but the role of Galectins in hUC-MSCs differentiation and osteogenic differentiation is unclear. The expression changes in differentiation and osteogenic differentiation provide a theoretical basis for further study of hUC-MSCs differentiation. Methods: (1) isolation and purification of human umbilical cord mesenchymal stem cells, using flow cytometry to detect the immunophenotype of mesenchymal stem cells, oil red O staining, Von Kossa staining and alizarin red staining to observe the lipid fractions. Differentiation and identification of hUC-MSCs, and (2) RT-PCR semi quantitative detection of the expression changes in hUC-MSCs Galectins members (Gal-1, Gal-2, Gal-3, Gal-4, Gal-7, Gal-8, Gal-9, Gal-10, Gal-9, etc.), and to screen out their high expression subtypes; (3) The expression of Gal-1, Gal-3, Gal-8 and Gal-9 mRNA in the interval (zeroth days, 1 days, 3 days, 7 days, 14 days and 21 days); (4) to collect the cell culture supernatant in the process of lipid differentiation and osteogenesis, and to detect the expression of Gal-1 and Gal-9 secreted protein by ELISA. Results: (1) hUC-MSCs high expression D29, CD73, CD73, CD73 6 and HLA-ABC, do not express CD14, CD31, CD45, CD133 and HLA-DR, and have the ability to differentiate into adipocytes and osteoblasts in vitro. (2) hUC-MSCs cells express Gal-1, Gal-3, Gal-7, Gal-8, Gal-7, and subtypes in Galectins family. Gal-9 mRNA gradually decreased with the induction time during the differentiation and osteogenic differentiation of hUC-MSCs, while Gal-3mRNA and Gal-8 mRNA increased with the induction time in the process of lipid differentiation and osteogenic differentiation of hUC-MSCs. (4) ELISA detection suggested that Gal-1 and Gal-9 may be divided into hUC-MSCs fat differentiation and osteogenic differentiation through external secretions. Conclusion: the expression of Galecins (Gal-1, Gal-3, Gal-8 and Gal-9) changes obviously in the process of lipid differentiation and osteogenesis differentiation of hUC-MSCs, in which Gal-1 and Gal-9 may play a role through exocrine, which provides a theoretical basis for further study of the role of Galectins in hUC-MSCs differentiation.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R329.2

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