本文關(guān)鍵詞：小鼠間充質(zhì)干細(xì)胞抑制急性移植物抗宿主病的機(jī)制　出處：《中國(guó)人民解放軍軍事醫(yī)學(xué)科學(xué)院》2008年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 間充質(zhì)干細(xì)胞 急性移植物抗宿主病 T淋巴細(xì)胞 樹突狀細(xì)胞 遷移

【摘要】： 間充質(zhì)干細(xì)胞(MSC)是最先從骨髓中分離出來的一群具有自我更新和多向分化潛能的成體干細(xì)胞。近年來許多學(xué)者在骨髓以外的組織器官中也分離出MSC,包括肌肉、脂肪、骨實(shí)質(zhì)、胰腺、胸腺、肺臟、臍帶和胎盤等幾乎機(jī)體所有的組織和器官。MSC在特定的誘導(dǎo)條件下能夠向骨、軟骨、脂肪、肌肉等多種間充質(zhì)系統(tǒng)細(xì)胞分化;體外和體內(nèi)實(shí)驗(yàn)均證明了MSC及其分化細(xì)胞可給予造血細(xì)胞結(jié)構(gòu)和功能上的支持,具有造血支持作用。MSC具有的這些功能使之成為了組織工程和骨髓移植細(xì)胞治療的研究熱點(diǎn)。造血干細(xì)胞移植是一些難治性血液病(白血病、再障、免疫缺損病、極重度放射病等)最有效且唯一的解決途徑。急性移植物抗宿主病(aGvHD)是異體造血干細(xì)胞移植(allo-HSCT)常見的并發(fā)癥和死亡原因。近年來,MSC強(qiáng)大的免疫調(diào)節(jié)功能逐漸受到人們的重視,這促使了MSC進(jìn)入臨床應(yīng)用于aGvHD的治療。目前,療效良好,在美國(guó)已進(jìn)入Ⅲ期臨床。但由于小鼠MSC分離和培養(yǎng)困難的瓶頸,限制了MSC用于常用的小鼠模型進(jìn)行體內(nèi)免疫調(diào)節(jié)功能機(jī)制的研究。 本研究的主要目的是探討小鼠骨實(shí)質(zhì)MSC的生物學(xué)特性及其抑制aGvHD的機(jī)制。具體研究?jī)?nèi)容包括建立一種新的小鼠MSC分離培養(yǎng)的方法—膠原酶消化后的骨實(shí)質(zhì)分離小鼠MSC,并對(duì)細(xì)胞的一般形態(tài)、免疫表型、分化能力、支持造血和免疫調(diào)節(jié)功能進(jìn)行鑒定;建立小鼠aGvHD模型,給予模型小鼠尾靜脈共輸注MSC,觀察輸注后小鼠平均生存時(shí)間,病理變化確定MSC抑制aGvHD的效果,并在此基礎(chǔ)上對(duì)MSC抑制aGvHD的體內(nèi)機(jī)制作進(jìn)一步探討。 本實(shí)驗(yàn)中,采用了骨片消化法分離培養(yǎng)小鼠MSC。培養(yǎng)中,纖維樣的細(xì)胞從骨片周圍爬出,漸漸長(zhǎng)滿瓶皿;這些細(xì)胞有較均一的表型,是一群非造血(CD45~-),非巨噬(CD11b~-),非內(nèi)皮(CD31~-),僅表達(dá)一些細(xì)胞粘附分子(CD29~+、CD44~+、CD105~+)的干細(xì)胞(Sca-1~+)群體,經(jīng)傳代后能夠保持較穩(wěn)定的細(xì)胞表型;具有較穩(wěn)定的克隆形成能力;經(jīng)誘導(dǎo)能夠向脂肪、成骨、軟骨細(xì)胞分化。進(jìn)一步對(duì)這種方法培養(yǎng)的細(xì)胞進(jìn)行功能檢測(cè),結(jié)果表明:它們體外具有與骨髓基質(zhì)細(xì)胞相似的造血支持功能和抑制ConA或異種細(xì)胞刺激的淋巴細(xì)胞增殖的能力。MSC輸注可延長(zhǎng)異種皮膚移植的平均生存時(shí)間,說明此種小鼠骨實(shí)質(zhì)來源的MSC具有體內(nèi)免疫調(diào)節(jié)能力。 aGvHD發(fā)生的病理生理過程可劃分為三個(gè)階段。階段Ⅰ:預(yù)處理作用,在移植之前的放化療作用造成機(jī)體上皮和內(nèi)皮的損傷,使抗原呈遞細(xì)胞(APC)活化成熟;階段Ⅱ:供者T細(xì)胞接受APC呈遞的抗原,活化,增殖;階段Ⅲ:炎性因子和細(xì)胞殺傷作用損傷靶器官。機(jī)體的損傷可進(jìn)一步活化APC,使疾病進(jìn)入一個(gè)漸進(jìn)的惡性循環(huán),所以,aGvHD一旦發(fā)生,就很難控制。應(yīng)用異種脾細(xì)胞尾靜脈輸注建立小鼠aGvHD模型,發(fā)現(xiàn)MSC共輸注延長(zhǎng)了aGvHD小鼠的平均生存時(shí)間,并呈劑量依賴關(guān)系;改善了aGvHD小鼠靶器官的病理改變。進(jìn)一步的對(duì)脾細(xì)胞表型及功能的檢測(cè)表明:MSC輸注降低了aGvHD小鼠脾臟CD11b~+細(xì)胞MHCⅡ和早期活化分子CD69的表達(dá);降低了CD3~+細(xì)胞早期活化分子CD69的表達(dá)和脾細(xì)胞的增殖;降低了脾細(xì)胞的殺傷功能。MSC提高了脾臟CD4~+細(xì)胞的比例,晚期降低了CD8~+細(xì)胞的比例,從而明顯提高了CD4~+/CD8~+的比值;CD4~+CD25~+調(diào)節(jié)性T細(xì)胞(Tregs)活化后表達(dá)FoxP3,臨床觀察,aGvHD患者單獨(dú)Tregs數(shù)量與疾病嚴(yán)重程度無相關(guān)性,原因在于aGvHD患者存在著Tregs的數(shù)量嚴(yán)重減少和T淋巴細(xì)胞的大量增殖。Tregs的靶細(xì)胞是CD8~+T淋巴細(xì)胞,患者的外周血和靶器官FoxP3~+/CD8~+的比值與疾病嚴(yán)重程度有密切的相關(guān)性。我們的實(shí)驗(yàn)結(jié)果與此相互驗(yàn)證:MSC僅略微提高了Tregs的比例,但Tregs/CD8~+的比值卻被顯著提高。 aGvHD的發(fā)生發(fā)展有三個(gè)必要條件,是在1966年界定的Billingham三原則:1.宿主必須處于免疫抑制或缺陷狀態(tài);2.移植物中含有免疫功能的細(xì)胞;3.宿主和供者之間存在著不相容性抗原。在1989年提出,并在1993年確定并加入的第四條原則:效應(yīng)細(xì)胞必須能遷移到aGvHD靶器官,稱為Billingham的修訂原則,此修訂原則強(qiáng)調(diào)了效應(yīng)細(xì)胞遷移到aGvHD靶器官的重要性。令我們感興趣的是:MSC輸注增加了aGvHD小鼠二級(jí)淋巴器官(SLO)的T淋巴細(xì)胞的數(shù)量。表達(dá)CD62L和CCR7分子是T淋巴細(xì)胞進(jìn)入SLO的先決條件。體外的混合淋巴細(xì)胞反應(yīng)中,MSC的存在,使T細(xì)胞(包括Tregs)保持了幼稚細(xì)胞的表型(CD62L~+/CCR7~+),并且保持了這些細(xì)胞的由二級(jí)淋巴組織趨化因子(SLC)引導(dǎo)的細(xì)胞遷移。樹突狀細(xì)胞(DC)是體內(nèi)免疫反應(yīng)的啟動(dòng)者,表達(dá)CCR7對(duì)DC的成熟并進(jìn)一步向SLO遷移至關(guān)重要。在體外DC誘導(dǎo)過程中,MSC的存在降低了DC的CD80、CD86、CD40、CDIa~b的表達(dá)并明顯降低了CCR7的表達(dá),并且這種DC向SLC的遷移作用也相應(yīng)的減弱。以上過程主要是通過MSC分泌的可溶性分子來實(shí)現(xiàn)的。T細(xì)胞活化和DC的遷移功能的發(fā)揮總是與細(xì)胞骨架重排相伴行的。MSC共培養(yǎng)減少了T細(xì)胞極化和偽足的形成,減少了DC的極化和樹突的形成,降低其相關(guān)信號(hào)通路蛋白R(shí)acl和Cdc42的活化可能使其原因。相一致地,MSC輸注使aGvHD小鼠SLO中T細(xì)胞保持了幼稚(CD62L~+/CCR7~+)的表型,并且降低了SLO中DC的比例和CCR7的表達(dá)。用轉(zhuǎn)入eGFP的MSC輸注來示蹤輸注后MSC的體內(nèi)分布,發(fā)現(xiàn)MSC主要分布于外周組織和器官,而極少進(jìn)入SLO,MSC極少表達(dá)CD62L和CCR7可能是這一現(xiàn)象的原因。 綜上所述,此種簡(jiǎn)單易行方法所培養(yǎng)的小鼠骨實(shí)質(zhì)MSC,符合MSC的特征,具有MSC功能,可進(jìn)一步用于小鼠生理和病理模型的研究;MSC從aGvHD發(fā)-生的三個(gè)階段均能抑制其發(fā)展,改變T淋巴細(xì)胞亞群的比例可能是MSC體內(nèi)發(fā)揮免疫調(diào)節(jié)的機(jī)制之一;通過改變T和DC的遷移功能對(duì)MSC抑制aGvHD起到了重要作用。 本研究的創(chuàng)新點(diǎn):1.應(yīng)用一種新方法培養(yǎng)小鼠MSC,突破了小鼠MSC培養(yǎng)困難的瓶頸;2.將MSC應(yīng)用于小鼠aGvHD模型,進(jìn)行MSC體內(nèi)免疫調(diào)節(jié)功能的機(jī)制探討;3.發(fā)現(xiàn)MSC在體外,體內(nèi)均能改變T細(xì)胞和DC的遷移功能,此改變是MSC抑制aGvHD的機(jī)制之一。 此研究對(duì)MSC移植發(fā)揮體內(nèi)免疫調(diào)節(jié)的機(jī)制提供了新線索,為MSC更好地應(yīng)用于臨床治療奠定基礎(chǔ)。
[Abstract]:Mesenchymal stem cells (MSC) were isolated from bone marrow of a group of self-renewal and multilineage differentiation potential of adult stem cells. In recent years, many scholars in the bone marrow tissues also isolated MSC, including muscle, fat, bone substance, pancreas, thymus, lung, umbilical cord and placenta. Almost all body tissues and organs of.MSC to bone, cartilage, fat in the induction of specific conditions, such as muscle mesenchyme cell differentiation; in vitro and in vivo experiments have demonstrated the MSC and differentiated cells can give hematopoietic cell structure and function support, support hematopoiesis.MSC has these features enable it has become a research hotspot in tissue engineering and cell therapy. Bone marrow transplantation of hematopoietic stem cell transplantation is some refractory hematological diseases (leukemia, aplastic anemia, immunodeficiency disease, severe radiation sickness etc.) the most effective and unique solution No way. Acute graft-versus-host disease (aGvHD) is allogeneic hematopoietic stem cell transplantation (allo-HSCT) common complications and causes of death. In recent years, immune MSC strong regulatory function has attracted more and more attention. This prompted the MSC treatment in clinical application in aGvHD. At present, the United States has good curative effect. In phase III clinical. But because of the mouse MSC isolate and culture difficult bottleneck, restrict the research on MSC in murine model of in vivo immune mechanism.
The main purpose of this study is to explore the biological characteristics mechanism of mouse bone MSC and inhibition of aGvHD. The research contents include bone substance isolated from mouse MSC after collagenase digestion method and establish a novel mouse MSC were isolated, and the general form of cell immunophenotype, differentiation ability, support hematopoiesis and immune identification regulating function; establish the mouse model of aGvHD, given the model of mouse tail vein infusion of MSC were observed after infusion, average survival time of mice, the pathological changes of MSC inhibit the effects of aGvHD, to further explore the in vivo of MSC inhibiting aGvHD production and on this basis.
In this experiment, using a bone chip digestion method of isolation and culture of mouse MSC. fibroblast like cells in culture, to climb out from the bone around, gradually covered the bottle dish; these cells have the phenotype of a uniform, is a group of non hematopoietic (CD45~-), non macrophage (CD11b~-), endothelium (CD31~-), only the expression of some cell adhesion molecules (CD29~+, CD44~+, CD105~+) stem cells (Sca-1~+) group, after passage can maintain a stable phenotype; with stable clone forming ability; Osteogenic induced by fat, cartilage cell differentiation. Further these cells function test results they show that in vitro with the average survival time is similar to bone marrow stromal cells support hematopoiesis function and inhibit ConA or xenogeneic cells stimulated lymphocytes proliferation ability of.MSC infusion can prolong the xenograft skin, the mouse bone from MSC It has the ability to regulate the immune system in the body.
The pathophysiological process of the occurrence of aGvHD can be divided into three stages. The first phase: effect of pretreatment, the epithelial and endothelial damage caused by chemotherapy in action before transplantation, the antigen presenting cells (APC) activation; stage II: donor T cells underwent APC antigen presentation, activation, proliferation; phase III the inflammatory factors and cell killing effect of damage to the target organ. The damage of organism can further activate APC, bringing the disease into a progressive vicious spiral, so once aGvHD occurs, it is difficult to control. The application of intravenous injection of xenogeneic spleen cells in mice aGvHD model showed that MSC co infusion prolonged the average survival time of aGvHD mice, in a dose-dependent manner; improve the pathological changes of target organs of aGvHD mice. The spleen cells showed that the phenotype and function of further MSC infusion reduced aGvHD mouse spleen CD11b~+ cells and early activation of MHC II The expression of CD69 molecules; reduce early CD3~+ cell proliferation and activation of CD69 molecules and expression of spleen cells; reduce the spleen cell killing function of.MSC increased the proportion of CD4~+ cells in spleen, late reduced the proportion of CD8~+ cells, resulting in a significant increase of the ratio of CD4~+/CD8~+; CD4~+CD25~+ regulatory T cells (Tregs) expression and clinical observation FoxP3, after activation, no correlation with aGvHD Tregs alone the number and severity of disease in patients with aGvHD due to the number of Tregs CD8~+ is severely reduced T lymphocyte target cell proliferation of.Tregs and T lymphocytes, there was a close correlation between the ratio of patients with disorders of the peripheral blood and the severity of target organ of FoxP3~+/CD8~+. We the experimental results and the mutual authentication: MSC only slightly increased the proportion of Tregs, but the ratio of Tregs/CD8~+ was significantly increased.
There are three necessary conditions for the occurrence and development of aGvHD in 1966, is defined by the Billingham three principles: 1. host must be in immunodeficiency state; immune function contains 2. cells in the graft; 3. between host and donor incompatible with antigen. In 1989, fourth principles and determined to join in 1993: effector cells must be able to migrate to the target organ of aGvHD, known as the revised Billingham principles, this revision principle emphasizes the importance of the aGvHD effect cells migrate to target organs. It is interesting for us: MSC infusion increased aGvHD mice two secondary lymphoid organs (SLO) the number of T lymphocytes and CD62L. The expression of CCR7 is a prerequisite for T cell into SLO. The mixed lymphocyte reaction in vitro in the presence of MSC, T cells (including Tregs) maintain phenotype of immature cells (CD62L~+/CCR7~+), and keep these The cell is composed of two lymphoid tissue chemokine (SLC) cell migration guide. Dendritic cells (DC) is an immune response in the body to start, CCR7 on the maturation of DC expression and further to SLO migration is essential. In vitro induced by DC in the process of MSC was decreased in the presence of DC CD80, CD86, CD40. The expression of CDIa~b and decreased the expression of CCR7, DC and the migration effect of SLC also decreased. The above process is the main migration function of soluble molecules through the secretion of MSC to achieve the.T cell activation and DC play is always accompanied with the cytoskeletal rearrangement of.MSC co culture to reduce the formation of T cell polarization and actin, reducing the formation of polarization and dendritic DC, reduce the activation of the signal pathway related proteins Racl and Cdc42 may be the reason. Consistently, MSC infusion of T cells in aGvHD mice SLO keep the naive (CD62L~+/CCR7~+) Phenotypes, and reduced the proportion of DC and CCR7 expression in SLO. The MSC distribution in eGFP was used to trace the distribution of MSC after infusion. It was found that MSC was mainly distributed in peripheral tissues and organs, but rarely entered SLO. MSC rarely expressed CD62L and CCR7, which may be the reason for this phenomenon.
In conclusion, this simple method of cultured mouse bone MSC, with the characteristics of MSC, with MSC function, can be used for further research of the physiology and pathology of mice; MSC from aGvHD - three stage students can restrain the development and changes of T lymphocyte subsets ratio may be one mechanism of in vivo MSC immune regulation; through the migration function changes of T and DC on the inhibition of MSC aGvHD played an important role.
The innovation of this research: 1. the application of a new method of culturing mouse MSC, break through the bottleneck of the difficulty in the culture of mouse MSC; 2. the application of MSC in a rat model of aGvHD, discusses the mechanism of MSC in immune function; 3. MSC in vitro, and in vivo changes of T cells and DC transfer function, this change is one of the mechanisms of MSC inhibition of aGvHD.
This study provides new clues for the mechanism of MSC transplantation to play the immune regulation in the body and lays the foundation for the better application of MSC to clinical treatment.

【學(xué)位授予單位】：中國(guó)人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2008
【分類號(hào)】：R329

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