本文選題：間充質(zhì)干細胞 + 細胞移植　； 參考：《中國人民解放軍軍事醫(yī)學科學院》2015年碩士論文

【摘要】：缺血性心臟病(ischemic heart disease,IHD)是威脅人類健康的主要殺手之一,具有極高的致死率和致殘率[1]。盡管多數(shù)患者能從經(jīng)皮冠狀動脈腔內(nèi)血管成形術(shù)(percutaneous transluminal coronary angioplasty,PTCA)、冠狀動脈搭橋手術(shù)(coronary artery bypass graft,CABG)及藥物治療中獲益,但仍然有相當數(shù)量的慢性缺血性心臟病(chronic ischemic heart disease,CHD)患者,他們因為冠脈病變嚴重、彌漫等各種原因無法進行手術(shù)治療,且藥物治療效果往往不理想[2]。這部分CHD患者目前缺乏有效的干預(yù)措施,臨床上也被稱作“無選擇權(quán)”患者。干細胞研究的進展為這類患者帶來了希望。近年來,大量基礎(chǔ)[3,4]和臨床研究[5,6]顯示,干細胞移植可以減少心肌細胞凋亡,促進新生血管形成,改善心室重構(gòu),提高心功能,顯示出良好的應(yīng)用前景。其中間充質(zhì)干細胞(mesenchymal stem cells,MSCs)因其來源廣泛,操作簡便,具有免疫豁免效應(yīng)等優(yōu)勢而受到研究人員的廣泛青睞。現(xiàn)有的研究表明,MSCs治療急性心肌缺血安全有效。但MSCs在治療慢性心肌缺血方面的研究尚少。目前,國內(nèi)外尚未見到在大動物模型上研究聯(lián)合移植MSCs治療CHD的報道。MSCs有多種來源,現(xiàn)有的研究多采用骨髓來源間充質(zhì)干細胞(bone marrow-derived mesenchymal stem cells,BM-MSCs)。但BM-MSCs具有取材有創(chuàng)傷,年齡較大供體的MSCs增殖能力有限等缺點[7,8]。因此,研究人員開始探討多種其他來源MSCs治療心臟病的可行性。其中臍帶來源間充質(zhì)干細胞(umbilical cord-derived mesenchymal stem cells,UC-MSCs)因其取材無創(chuàng)傷,無倫理限制,細胞增殖和分化能力強,能分泌多種促血管生成因子等優(yōu)勢,成為替代BM-MSCs的較為理想的細胞來源[9]。目前已經(jīng)有大量采用UC-MSCs治療多種疾病的臨床前或臨床研究報道,包括肝硬化[10]、糖尿病[11]、系統(tǒng)性紅斑狼瘡[12]、移植物抗宿主病(graft-versus-host disease,GVHD)[13]等,但在心臟病的研究方面尚處于起步階段。目前尚未見到采用UC-MSCs治療CHD的研究報道。因此,本研究擬建立豬慢性缺血性心臟病動物模型,通過冠脈結(jié)合兩次靜脈輸注的方式移植異體豬骨髓來源間充質(zhì)干細胞(pig bone marrow-derived mesenchymal stem cells,p BM-MSCs)和人臍帶來源間充質(zhì)干細胞(human umbilical cord-derived mesenchymal stem cells,h UC-MSCs)進行干預(yù),采用冠脈造影、心臟超聲、單光子發(fā)射計算機斷層成像(single-photon emission computed tomography,SPECT)和病理組織學等方法綜合評價骨髓和臍帶來源MSCs移植對CHD的治療作用,從而為今后的臨床應(yīng)用提供依據(jù)。本研究首先采用Ficoll密度梯度法分離p BM-MSCs,相差顯微鏡觀察顯示,p BM-MSCs呈梭形,旋渦狀或魚尾狀生長。流式檢測結(jié)果表明,p BM-MSCs表達CD44、CD29、CD90,而CD14、CD34、CD45、CD166、HLA-DR表達呈陰性。誘導分化實驗發(fā)現(xiàn),p BM-MSCs能夠分化為脂肪細胞、成骨細胞、軟骨細胞。然后我們采用酶消化法分離h UC-MSCs,相差顯微鏡下觀察,細胞呈梭形,旋渦狀或平行排列,流式檢測結(jié)果顯示,細胞表達CD29、CD44、CD73、CD90、CD105和HLA-ABC,而CD34、CD45、HLA-DR表達呈陰性。誘導分化結(jié)果顯示,h UC-MSCs可向脂肪細胞、成骨細胞和軟骨細胞的分化。最后我們著重探討了p BM-MSCs和h UC-MSCs對慢性缺血性心臟病大動物模型的治療作用。選取30只小型豬,將Ameroid動脈縮窄環(huán)置于豬左冠回旋支(left circumflex coronary artery,LCX)建立慢性缺血性心臟病動物模型,4周后通過冠脈造影和心電圖對模型進行評價;存活的20只動物隨機分為p BM-MSCs組(n=8)、h UC-MSCs組(n=6)和對照組(n=6),治療組采用冠脈結(jié)合兩次靜脈輸注的方式移植經(jīng)過CM-Di I標記的p BM-MSCs和h UC-MSCs進行干預(yù),對照組則輸注生理鹽水。細胞移植前和移植后4周,冠脈造影檢測冠脈側(cè)枝循環(huán),心臟超聲檢測心功能和心臟結(jié)構(gòu)指標,SPECT檢測心肌血流灌注。動物處死后取心臟行2,3,5-氯化三苯基四氮唑(2,3,5-triphenyl-2H-tetrazolium chloride,TTC)染色計算梗死面積,并選取梗死邊緣區(qū)的組織制備病理切片,檢測心肌細胞纖維化、凋亡、新生血管形成等情況,并觀察移植細胞的植入和轉(zhuǎn)歸。建模后4周,存活的20只豬冠脈造影顯示LCX均完全閉塞,心電圖可見Ⅰ、AVL和(或)Ⅱ、Ⅲ、AVF和(或)V4-V6導聯(lián)ST段壓低和(或)T波改變。細胞移植后4周,冠脈造影結(jié)果顯示:對照組和細胞治療組均有側(cè)枝血管形成,但與治療前相比,對照組Rentrop評分增加無統(tǒng)計學意義,而p BM-MSCs組和h UC-MSCs組結(jié)果則有顯著差異(p0.01),表明細胞移植促進了側(cè)枝循環(huán)的形成;與對照組相比,p BM-MSCs組和h UC-MSCs組側(cè)枝血管計數(shù)結(jié)果有顯著差異(P0.05),但兩個細胞治療組之間無明顯差別。心電圖結(jié)果表明,p BM-MSCs和h UC-MSCs移植組心率(heart rate,HR)較治療前無明顯變化,而對照組HR明顯增加(P0.01)。心臟超聲:細胞治療組的左室射血分數(shù)(Left ventricular ejection fraction,LVEF)較治療前均有升高,p BM-MSCs組從53.91%±6.72%升至58.19±7.10%(p0.05),h UC-MSCs組從56.12±2.86%升至61.32±3.23%(p0.05),而對照組的LVEF較治療前下降;與對照組相比,細胞治療組LVEF的升高具有顯著差異(P0.05),但p BM-MSCs組與h UC-MSCs組間相比無差異;與對照組相比,兩個細胞治療組的梗死區(qū)收縮期室壁增厚率(systolic thickening fraction in the infarcted left ventricular wall,WTh F)升高均有統(tǒng)計學差異(P0.05);此外,對照組的左室收縮末期容積(left ventricular end-systolic volume,LVESV)和左室舒張末期容積(left ventricular end-diastolic volume,LVEDV)較治療前均明顯增大(P0.05),而p BM-MSCs組和h UC-MSCs組治療前后未見明顯改變。SPECT結(jié)果顯示:對照組和細胞治療組心肌血流灌注均較治療前有所改善;但p BM-MSCs組(p0.01)和h UC-MSCs組(p0.05)改善較對照組明顯,且二者之間無顯著差異。病理組織學結(jié)果顯示,TTC染色:p BM-MSCs組和h UC-MSCs組梗死面積分別為7.89±2.62%和8.35±1.88%,比對照組(14.52±4.85%)顯著減小(p0.05);HE染色:細胞移植組炎性評分顯著低于對照組(p0.05);Masson三色染色顯示細胞移植組的膠原容積分數(shù)(collagen volume fraction,CVF)明顯小于對照組(p0.05);血管計數(shù):p BM-MSCs和h UC-MSCs移植組微血管密度顯著高于對照組(p0.05);TUNEL(terminal deoxynucleotidyl transferase d UTP nick end labeling)法檢測凋亡,p BM-MSCs組(11±3cells/100 cells)和h UC-MSCs組(13±4 cells/100cells)凋亡的心肌細胞數(shù)量明顯少于對照組(24±3 cells/100 cells)(p0.01)。熒光顯微鏡下梗死邊緣區(qū)可見有CM-Di I標記的細胞,免疫熒光染色顯示p BM-MSCs組和h UC-MSCs組均可見移植后的MSCs部分分化為血管內(nèi)皮細胞,未觀察到其向心肌細胞分化。RT-q PCR顯示,與對照組相比,p BM-MSCs組的促血管生成素(angiogenin,Ang)表達增高(p0.05),h UC-MSCs組的Ang(p0.01)和血管內(nèi)皮生長因子(vascular endothelial growth factor,VEGF)(p0.05)表達增高,而白介素-6(interleukin-6,IL-6)、成纖維細胞生長因子(fibroblast growth factor,FGF)、胸腺肽β4(thymosin beta 4,Tβ4)的表達無顯著改變。本研究成功分離培養(yǎng)了p BM-MSCs和h UC-MSCs;并將Ameroid動脈縮窄環(huán)置入豬LCX成功建立豬慢性缺血性心臟病模型;經(jīng)冠脈結(jié)合兩次靜脈輸注p BM-MSCs及h UC-MSCs治療研究結(jié)果表明,p BM-MSCs及h UC-MSCs均能有效減少梗死面積,減輕炎癥反應(yīng),減少心肌細胞凋亡和心肌纖維化,促進側(cè)枝循環(huán)形成及血管新生,改善心肌血流灌注,改善心室重構(gòu),提高心功能,且兩種細胞的治療作用無顯著差異。
[Abstract]:Ischemic heart disease (IHD) is one of the major killer of human health, with high mortality and disability rate [1]., although most patients can from percutaneous transluminal coronary angioplasty (percutaneous transluminal coronary angioplasty, PTCA), coronary artery bypass surgery (coronary artery) CABG) and the benefit of drug treatment, but there are still a considerable number of patients with chronic ischemic heart disease (chronic ischemic heart disease, CHD) who are unable to perform surgical treatment because of serious coronary lesions, diffuse and other reasons, and the effect of the drug treatment often fails to think of [2]., a part of the CHD patient currently lacking effective interventions. The bed is also known as "no choice". The progress of stem cell research has brought hope to these patients. In recent years, a large number of basic [3,4] and clinical studies [5,6] show that stem cell transplantation can reduce myocardial apoptosis, promote angiogenesis, improve ventricular remodeling, raise cardiac function, and show good prospects for application. Mesenchymal stem cells (MSCs) is widely favored by researchers because of its extensive origin, simple operation and immunity immunity effect. The present study shows that MSCs is safe and effective in the treatment of acute myocardial ischemia. However, there are few studies on the treatment of chronic myocardial ischemia by MSCs. At present, it has not been seen at home and abroad at home and abroad. There are a variety of sources for the study of the combined transplantation of MSCs for the treatment of CHD in the animal model. The existing studies are mostly using bone marrow derived mesenchymal stem cells (bone marrow-derived mesenchymal stem cells, BM-MSCs). But BM-MSCs has the disadvantages of being traumatic, and the MSCs colonization of older donors is limited. The feasibility of various other sources of MSCs for the treatment of heart disease is discussed. Among them, the umbilical cord derived mesenchymal stem cells (umbilical cord-derived mesenchymal stem cells, UC-MSCs) are ideal for replacing BM-MSCs because of their noninvasive, non ethical limitations, strong cell proliferation and differentiation, and the ability to secrete a variety of angiogenic factors. Cell source [9]. now has a large number of pre clinical or clinical reports on the use of UC-MSCs for various diseases, including liver cirrhosis [10], diabetic [11], systemic lupus erythematosus [12], graft-versus-host disease, GVHD [13] and so on, but it is still in the initial stage of heart disease research. UC-MSCs for the treatment of CHD is reported. Therefore, this study is to establish a porcine chronic ischemic heart disease animal model, transplanting allogenic pig bone marrow derived mesenchymal stem cells (pig bone marrow-derived mesenchymal stem cells, P BM-MSCs) and human umbilical cord derived mesenchymal stem cells (human umbilical) by two intravenous infusion of coronary artery. Ord-derived mesenchymal stem cells, H UC-MSCs) intervention, using coronary angiography, cardiac ultrasound, single photon emission computed tomography (single-photon emission computed tomography, SPECT) and histopathology to evaluate the therapeutic effect of MSCs transplantation on bone marrow and umbilical cord sources for future clinical applications. Firstly, the Ficoll density gradient method was used to separate P BM-MSCs, and the phase microscope observation showed that P BM-MSCs was spindle shaped, vortexed or fish tail like growth. The flow test results showed that P BM-MSCs expressed CD44, CD29, CD90, while CD34, CD34, and CD90 were negative. Adipose cells, osteoblasts, chondrocytes. Then we use enzyme digestion method to separate h UC-MSCs. Under phase contrast microscope, the cells are spindle shaped, vortexed or parallel arrangement. Flow cytometry results show that cells express CD29, CD44, CD73, CD90, CD105 and HLA-ABC, and CD34, CD45, HLA-DR expression is negative. The differentiation of adipose cells, osteoblasts and chondrocytes. Finally, we focused on the therapeutic effect of P BM-MSCs and H UC-MSCs on the large animal model of chronic ischemic heart disease. 30 small pigs were selected and the Ameroid artery coarctation ring was placed in the left circumflex branch of the pig (left circumflex coronary artery, LCX) to establish a chronic ischemic heart disease animal model. The model was evaluated by coronary angiography and electrocardiogram after 4 weeks. The 20 surviving animals were randomly divided into P BM-MSCs group (n=8), H UC-MSCs group (n=6) and control group (n=6). The treatment group was transplanted with CM-Di I marked P BM-MSCs and h, and the control group was transfused with saline. Coronary collateral circulation was detected by coronary angiography before and 4 weeks after transplantation. Cardiac function and cardiac structure were detected by echocardiography. Myocardial perfusion was detected by SPECT. The infarct area was calculated by 2,3,5- chlorination of three phenyl tetrazoles (TTC) after the death of the animals, and the marginal area of the infarct was selected. Pathological sections were prepared to detect myocardial fibrosis, apoptosis, neovascularization, and the implantation and outcome of the transplanted cells. 4 weeks after modeling, 20 surviving porcine coronary angiography showed that LCX was completely obliterate, and the electrocardiogram showed I, AVL and (or) II, AVF and (or) V4-V6 lead ST segment depression and (or) T wave changes. Cell transplantation After 4 weeks, the results of coronary angiography showed that there were collateral vessels in both the control group and the cell therapy group, but the Rentrop score in the control group was not statistically significant compared with the control group, while the results in the P BM-MSCs group and the H UC-MSCs group were significantly different (P0.01), indicating that the cell transplantation promoted the formation of the collateral circulation; compared with the control group, the P BM-MSCs group and the control group were compared with the control group. There was a significant difference in the collateral vessel count results in the H UC-MSCs group (P0.05), but there was no significant difference between the two cell treatment groups. The ECG results showed that the heart rate (heart rate, HR) in the P BM-MSCs and H UC-MSCs transplantation group was not significantly higher than that before the treatment, while the control group was significantly increased (P0.01). Ricular ejection fraction, LVEF) was higher than that before treatment, P BM-MSCs group rose from 53.91% + 6.72% to 58.19 + 7.10% (P0.05), H UC-MSCs group rose from 56.12 + 2.86% to 61.32 + 3.23% (P0.05), while LVEF in control group was lower than before treatment, and the increase of LVEF in cell therapy group was significantly different from that of control group. There was no difference between the Cs groups. Compared with the control group, the thickening rate of the systolic ventricular wall of the two cell therapy group (systolic thickening fraction in the infarcted left ventricular wall, WTh F) was statistically different. And the left ventricular end diastolic volume (left ventricular end-diastolic volume, LVEDV) was significantly higher than before the treatment (P0.05), while the P BM-MSCs group and the H UC-MSCs group had no significant changes in.SPECT results before and after treatment: the myocardial perfusion in the control group and the cell treatment group was better than that before the treatment. .05) improved compared with the control group, and there was no significant difference between the two. The histopathological results showed that the infarct area of the P BM-MSCs group and the H UC-MSCs group was 7.89 + 2.62% and 8.35 + 1.88%, respectively, compared with the control group (14.52 + 4.85%), respectively (P0.05); HE staining: the inflammatory score of the cell transplantation group was significantly lower than that of the control group (P0.05); Masson tricolor staining was found. The collagen volume fraction (collagen volume fraction, CVF) in the color display cell transplantation group was significantly smaller than that of the control group (P0.05), and the blood vessel count: the microvascular density in the P BM-MSCs and H UC-MSCs transplantation group was significantly higher than that of the control group (P0.05). The number of apoptotic cardiomyocytes in group 100 cells) and H UC-MSCs group (13 + 4 cells/100cells) was significantly less than that of the control group (24 + 3 cells/100 cells) (P0.01). There was CM-Di I labeled cells in the marginal area of the infarct under the fluorescence microscope. The immunofluorescence staining showed that the P BM-MSCs group and the H group were all differentiated into vascular endothelial cells. .RT-q PCR showed that the expression of angiopoietin (angiogenin, Ang) in the P BM-MSCs group was higher than that of the control group (P0.05), and the expression of Ang (P0.01) and vascular endothelial growth factor in the H UC-MSCs group was higher than that of the control group. The expression of fibroblast growth factor (FGF) and thymosin beta 4 (thymosin beta 4, T beta 4) had no significant changes. This study successfully isolated and cultured P BM-MSCs and H UC-MSCs, and succeeded in establishing a porcine chronic ischemic heart disease model by placing the contraction ring of the Ameroid artery. The results of MSCs therapy show that both P BM-MSCs and H UC-MSCs can effectively reduce infarct size, reduce inflammatory response, reduce myocardial apoptosis and myocardial fibrosis, promote the formation of collateral circulation and angiogenesis, improve myocardial perfusion, improve ventricular remodeling and improve cardiac function, and there is no significant difference in the therapeutic effect of two kinds of cells.

【學位授予單位】：中國人民解放軍軍事醫(yī)學科學院
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：R541

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