【摘要】：研究背景：糖尿病(Diabetes Mellitus,DM)是由于高血糖導(dǎo)致內(nèi)分泌代謝紊亂的全身性疾病,它能夠造成包括骨骼、神經(jīng)、腎臟等多器官多系統(tǒng)損傷。糖尿病患者胰島素相對(duì)或絕對(duì)缺乏,礦物質(zhì)組織代謝紊亂。無(wú)論是臨床還是實(shí)驗(yàn)研究均顯示,糖尿病能夠改變骨的生物力學(xué)性能、影響骨折的愈合。許多研究表明,糖尿病骨折愈合時(shí)間大約是非糖尿病患者的兩倍。每年雖然數(shù)以百萬(wàn)計(jì)的骨折發(fā)生,大多數(shù)治愈令人滿意,但仍有5%至10%會(huì)繼續(xù)延遲愈合或不愈合,甚至導(dǎo)致假關(guān)節(jié)形成或骨骼畸形,造成肢體功能障礙,嚴(yán)重影響患者的生活。因此如何治療糖尿病骨折日益受到人們的重視。人臍帶間充質(zhì)干細(xì)胞(human umbilical cord mesenchymal stem cells, hUCMSCs)和骨髓間充質(zhì)干細(xì)胞(human bone marrow MSCs, hBMSCs)一樣是一類具有自我更新和多向分化潛能的成體干細(xì)胞。但提取骨髓間充質(zhì)干細(xì)胞時(shí)需要有創(chuàng)操作,而且提取數(shù)量較少。另外,隨著年齡的增大,hBMSCs自我更新和增殖能力降低。最近,人臍帶間充質(zhì)干細(xì)胞越來(lái)越受到人們的關(guān)注,人臍帶間充質(zhì)干細(xì)胞可以向骨、軟骨、韌帶、肌腱、肌肉及脂肪等方向分化。其來(lái)源豐富,成本較低,而且無(wú)需有創(chuàng)操作。另外,hUCMSCs免疫排斥反應(yīng)較低,無(wú)腫瘤致畸性。因此其在組織工程、干細(xì)胞移植以及基因治療等領(lǐng)域具有廣闊的應(yīng)用前景,成為干細(xì)胞研究的熱點(diǎn),也為我們治療糖尿病骨折愈合提供了新的思路。糖尿病影響骨折愈合的原因較復(fù)雜,而細(xì)胞因子在骨折愈合過(guò)程中的改變是其中重要的因素之一。其中TGF-β1和 BMP-2在骨折愈合過(guò)程中具有非常重要的作用。研究表明：TGF-β1和BMP-2是骨重建和骨修復(fù)過(guò)程中重要的細(xì)胞因子。在骨折愈合過(guò)程中,TGF-β1促進(jìn)間充質(zhì)干細(xì)胞和成骨細(xì)胞的增值,BMP-2是膜內(nèi)成骨和軟骨內(nèi)化骨中非常重要的因子,其在骨折愈合過(guò)程中的研究較多,但是在糖尿病骨折愈合過(guò)程中的TGF-β1l和BMP-2的變化研究相對(duì)較少。應(yīng)用人臍帶間充質(zhì)干細(xì)胞治療糖尿病骨折愈合研究更少。我們應(yīng)用大鼠制作糖尿病骨折動(dòng)物模型,研究糖尿病骨折愈合過(guò)程中TGF-β1和BMP-2的變化。并應(yīng)用人臍帶間充質(zhì)干細(xì)胞,誘導(dǎo)分化為成骨細(xì)胞,然后移植到骨折部位,觀察糖尿病骨折愈合過(guò)程中TGF-p1和BMP-2的變化。為其臨床治療糖尿病骨折提供理論依據(jù)。研究目的：1.人臍帶間充質(zhì)干細(xì)胞的培養(yǎng)及成骨分化。2.糖尿病對(duì)骨折愈合的影響及TGF-pl和BMP-2在骨折愈合過(guò)程中的變化。3.人臍帶間充質(zhì)干細(xì)胞注射入骨折部位后,對(duì)糖尿病骨折愈合的影響。研究方法：1人臍帶間充質(zhì)干細(xì)胞的分離、鑒定及分化。1.1細(xì)胞培養(yǎng)人臍帶間充質(zhì)干細(xì)胞的分離、培養(yǎng)。獲取健康、足月、剖腹產(chǎn)胎兒臍帶,剝離臍帶wharton'sjelly膠,充分剪碎,酶消化法獲得臍帶間充質(zhì)干細(xì)胞,體外傳代、純化、擴(kuò)增,倒置顯微鏡下觀察細(xì)胞形態(tài)。1.2人臍帶間充質(zhì)干細(xì)胞的表面分子標(biāo)志檢測(cè)收集培養(yǎng)的第3代hUC-MSCs,加入CD14-PE.CD73.PE、CD105-PE.CD34-FITC..CD44-FITC.CD45-FITC.CD90-FITC.MHCⅡ-FITC單克隆抗體,1gGl-PE. 1gG1-FITC作為同型對(duì)照,24小時(shí)內(nèi)應(yīng)用流式細(xì)胞儀對(duì)細(xì)胞表面的CD分子進(jìn)行鑒定。1.3人臍帶間充質(zhì)干細(xì)胞的成骨分化及成脂分化1.3.1收集第3代hUC-MSCs,以成骨誘導(dǎo)培養(yǎng)基培養(yǎng),誘導(dǎo)7天后,行堿性磷酸酶染色；誘導(dǎo)分化21天后,進(jìn)行茜素紅染色,檢測(cè)鈣化基質(zhì)沉淀。1.3.2收集第3代hUC-MSCs,以脂肪誘導(dǎo)培養(yǎng)基培養(yǎng),誘導(dǎo)分化培養(yǎng)14天后,進(jìn)行油紅0染色。2糖尿病動(dòng)物骨折模型的制作。2.1糖尿病骨折動(dòng)物模型的制作及分組。雄性Wister大鼠75只隨機(jī)分為三組：糖尿病組(n=25)、HUCMSCs組(n=25)、正常對(duì)照組(n=25)。糖尿病組及HUCMSCs組大鼠腹腔注射四氧嘧啶(160mg/kg)建立糖尿病動(dòng)物模型,當(dāng)血糖濃度血糖大于16.7mmol/l,則為糖尿病大鼠模型誘導(dǎo)成功。中途死亡和造模失敗的大鼠再行造模補(bǔ)充,以保證每次每組用于檢測(cè)的大鼠數(shù)量為5只。糖尿病模型制作成功后,在無(wú)菌條件下將三組動(dòng)物均用手術(shù)方法于左脛骨上中1/3交界處用線據(jù)鋸斷脛骨人為造成左脛骨骨折。然后復(fù)位外固定。HUCMSCs組大鼠在骨折處用注射器穿刺至骨折端注射成骨誘導(dǎo)7天的第三代干細(xì)胞1x107個(gè)/Kg,正常對(duì)照組和糖尿病組注射等量的生理鹽水做為對(duì)照。2.2骨密度檢測(cè)對(duì)各組實(shí)驗(yàn)動(dòng)物在術(shù)后1周、2周、3周、4周、5周,每組隨機(jī)分別選取5只大鼠,然后使用DEXA骨密度儀掃描測(cè)定骨折處新生骨痂BMD,計(jì)算機(jī)記錄數(shù)據(jù)。檢測(cè)時(shí)骨密度儀設(shè)置為實(shí)驗(yàn)小動(dòng)物模式,以新生骨痂為中心由近至遠(yuǎn)掃描1厘米范圍,每組標(biāo)本測(cè)量三次,每次測(cè)量前都重置標(biāo)本,取平均值。2.3組織學(xué)及免疫組化學(xué)檢查手術(shù)后第1、2、3、4、5周,每組分別隨機(jī)抽取動(dòng)物各5只大鼠,麻醉狀態(tài)下以骨折端為中心,切取上下各0.5cm長(zhǎng)標(biāo)本,一半取出后立即放入液氮中儲(chǔ)存(用于熒光定量RT-PCR檢測(cè)),一半立即置入10%福爾馬林中固定24小時(shí),10%ED' A脫鈣、包埋完畢后,石蠟切片機(jī)將骨組織切成5μm厚切片。常規(guī)進(jìn)行病理切片的制作,免疫組化檢測(cè)按說(shuō)明書進(jìn)行。Leica-QwinV3圖像分析軟件檢測(cè)TGF-β1和BMP-2灰度值的變化。2.4熒光定量RT-PCR檢測(cè)每組5只脛骨骨痂樣本在液氮中取出后,進(jìn)行熒光定量RT-PCR檢測(cè)。qRT-PCR采用SYBR綠色PCR試劑盒,不加模板和反轉(zhuǎn)錄反應(yīng)物的做為陰性對(duì)照。用GAPDH作為RT-PCR的內(nèi)參,設(shè)定PCR程序。熒光定量PCR儀檢測(cè)相關(guān)數(shù)據(jù)并進(jìn)行分析。研究結(jié)果：1.采用酶消化法能有效分離純化hUCMSCs。接種24時(shí)后,貼壁細(xì)胞形態(tài)多為長(zhǎng)梭型、多邊形或成纖維細(xì)胞樣形態(tài)、大小均一,9天后成旋渦狀生長(zhǎng)。流式細(xì)胞儀分析,第3代細(xì)胞高表達(dá)CD44、CD73、CD90及CD105,低表達(dá)D14、CD34、CD45及MHCIⅠ。經(jīng)成骨誘導(dǎo)分化后堿性磷酸酶染色呈強(qiáng)陽(yáng)性,茜素紅染色可見(jiàn)明顯鈣結(jié)節(jié),油紅O染色可見(jiàn)胞漿中紅色的油滴。2.大鼠注射四氧嘧啶后,大部分在24-48 h后出現(xiàn)多飲、多食、多尿、血糖增高、呆滯、皮毛松散、體重下降等表現(xiàn),血糖大于16.7mmol/l,糖尿病模型造模成功。3.骨密度結(jié)果顯示：在術(shù)后第1周,三組大鼠骨痂局部骨密度測(cè)量值沒(méi)有明顯統(tǒng)計(jì)性差異(P0.05)；但在術(shù)后第2,3,4,5周,我們發(fā)現(xiàn)糖尿病大鼠組骨痂局部骨密度值隨著時(shí)間逐漸增加,但在相應(yīng)時(shí)間點(diǎn)其密度值明顯低于對(duì)照組,其差異具有統(tǒng)計(jì)學(xué)意義；hUC-MSCs組骨密度值在術(shù)后第2,3,4,5周高于糖尿病組,差異具備顯著性(P0.05),但是與對(duì)照組相比較,差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05)。4.組織學(xué)及免疫組化顯示：糖尿病鼠軟骨細(xì)胞及成骨細(xì)胞成熟延遲,骨痂形成較慢。免疫組化顯示：骨折后1-3周TGF-β1、 BMP-2在細(xì)胞內(nèi)廣泛表達(dá),特別是在骨痂和骨膜內(nèi),而糖尿病組骨痂組織中表達(dá)明顯低于正常組與hUC-MSCs治療組。hUCMSCs組和糖尿病組無(wú)明顯差別。5. BMP-2、TGF-β1實(shí)時(shí)熒光定量RT-PCR檢查顯示：正常組斷端骨癡組織BMP-2在第2周達(dá)高峰,而糖尿病組在第3周達(dá)高峰；正常組斷端骨癡組織TGF-β1在第3周達(dá)高峰,而糖尿病組在第4周達(dá)高峰；糖尿病組TGF-β1 BMP-2表達(dá)比正常對(duì)照組均推遲1周,BMP-2？TGF-β1在 hUC-MSCs組表達(dá)在第2、3周均較糖尿病組高,但和正常對(duì)照組相比差別不大。結(jié)論：1.在體外應(yīng)用酶消化法能獲得人臍帶間充質(zhì)干細(xì)胞,人臍帶間充質(zhì)干細(xì)胞具有多向分化能力,可分化為成骨細(xì)胞及脂肪細(xì)胞。2.糖尿病大鼠骨折后骨折愈合速度慢、愈合延遲。3.糖尿病降低骨折處骨痂骨密度,影響骨折部位骨痂形成。4.糖尿病明顯降低TGVF-β1、BMP-2表達(dá),進(jìn)而影響大鼠骨折處骨痂形成,是引起骨折愈合差的原因之一。5.應(yīng)用人臍帶間充質(zhì)干細(xì)胞治療后,糖尿病大鼠骨痂處細(xì)胞因子BMP-2、TGF-β1表達(dá)增多,骨密度提高,這可能是干細(xì)胞治療改善骨折愈合的分子機(jī)制之一,可為臨床治療糖尿病骨折提供理論支持。
[Abstract]:Background: Diabetes Mellitus (DM) is a systemic disease caused by hyperglycemia, which causes endocrine and metabolic disorders. It can cause multiple organ and multiple system injuries, including bone, nerve and kidney. Diabetes patients are relatively or absolutely deficient in insulin, and metabolic disorders of minerals and tissues. Both clinical and experimental studies show that sugar Urinary diseases can change the biomechanical properties of bone and affect the healing of fractures. Many studies have shown that the healing time of diabetic fractures is about two times that of non diabetic patients. Although millions of fractures occur each year, most of the healing is satisfactory, but 5% to 10% will continue to delay healing or nonunion and even lead to false joint formation. Human umbilical cord mesenchymal stem cells (hUCMSCs) and bone marrow mesenchymal stem cells (human bone marrow MSCs, hBMSCs) are the same kind of self as a kind of self. Adult stem cells are updated and pluripotent. But the extraction of bone marrow mesenchymal stem cells requires invasive operation and less extraction. In addition, as the age increases, the ability of hBMSCs to renew and proliferate is reduced. Recently, human umbilical cord mesenchymal stem cells are becoming more and more concerned. Human umbilical cord mesenchymal stem cells can be treated to bone. The cartilage, ligaments, tendons, muscles and fat are differentiated. They are rich in origin, low in cost, and without invasive operation. In addition, hUCMSCs has low immune rejection and no tumor teratogenicity. Therefore, it has a broad application prospect in the fields of tissue engineering, stem cell transplantation and gene therapy, which has become a hot spot in stem cell research. We have provided new ideas for the treatment of fracture healing of diabetes. The causes of diabetes affecting fracture healing are complex, and the change of cytokines during the healing process is one of the most important factors. TGF- beta 1 and BMP-2 have a very important role in the healing process. Research shows that TGF- beta 1 and BMP-2 are bone remodeling and bone remodeling. TGF- beta 1 promotes the growth of mesenchymal stem cells and osteoblasts in the process of fracture healing. BMP-2 is a very important factor in the osteogenesis and endochondral osseous bone in the membrane. It has been studied more during the process of fracture healing, but the change of TGF- beta 1L and BMP-2 during the healing process of diabetes mellitus The study is relatively less. The application of human umbilical cord mesenchymal stem cells in the treatment of diabetic fracture healing is less. We used rats to make a diabetic fracture animal model to study the changes of TGF- beta 1 and BMP-2 during the healing process of diabetes. To observe the changes of TGF-p1 and BMP-2 during the healing process of diabetic fracture. To provide a theoretical basis for the clinical treatment of diabetes fractures. Objective: the study of 1. human umbilical cord mesenchymal stem cells and the effect of osteogenic differentiation of.2. diabetes on fracture healing and the changes of TGF-pl and BMP-2 during the fracture healing process,.3. human umbilical cord mesenchymal stem cells were injected. The effect of the fracture site on the healing of diabetic fracture. Research methods: isolation, identification and differentiation of human umbilical cord mesenchymal stem cells from 1 human umbilical cord mesenchymal stem cells, isolation and culture of human umbilical cord mesenchymal stem cells cultured in.1.1 cells. Obtaining healthy, full month, Caesarean birth umbilical cord, stripping umbilical cord wharton'sjelly glue, full scissors and enzyme digestion to obtain umbilical cord mesenchymal Stem cells, external generation, purification, amplification, and inverted microscope observation of cell morphology.1.2 human umbilical cord mesenchymal stem cells surface molecular markers detection collected and cultured third generation of hUC-MSCs, adding CD14-PE.CD73.PE, CD105-PE.CD34-FITC..CD44-FITC.CD45-FITC.CD90-FITC.MHC II -FITC monoclonal antibody, 1gGl-PE. 1gG1-FITC as the same type control, 2 In 4 hours, CD molecules on the cell surface were identified by flow cytometry to identify the osteogenic differentiation and lipid differentiation of.1.3 human umbilical cord mesenchymal stem cells. 1.3.1 collected third generation of hUC-MSCs for osteogenic induction culture. After 7 days of induction, alkaline phosphatase staining was performed. Alizarin red staining was performed for 21 days after induction of differentiation, and calcified matrix was detected to precipitate.1.. 3.2 third generations of hUC-MSCs were collected with fat induced culture medium and 14 days after induction of differentiation and culture. The animal model of.2 diabetes animal fracture was made and grouped by oil red 0. 75 male Wister rats were randomly divided into three groups: diabetes group (n=25), HUCMSCs group (n=25), normal control group (n=25). Diabetes mellitus (n=25). The diabetic rat model was established by intraperitoneal injection of four pyrimidine (160mg/kg) in the disease group and the HUCMSCs group. When the blood glucose concentration was greater than 16.7mmol/l, the diabetic rat model was successfully induced. The midway death and the failure of the rat model were supplemented to ensure that the number of rats used in each group was 5. After success, the three groups of animals were operated on the 1/3 junction of the left tibia at the upper and middle tibia at the left tibia to cause the fracture of the left tibia in the upper and middle of the left tibia at the upper and middle tibia at the left tibia. Then the.HUCMSCs group was fixed at the fracture site and injected into the fracture end by injecting the syringe to the fracture end to induce the third generation of the third generation stem cells (1x107 /Kg), the normal control group and the diabetes. The disease group was injected with the same amount of physiological saline for the control of.2.2 bone density test for 1 weeks, 2 weeks, 3 weeks, 4 weeks, 5 weeks, each group randomly selected 5 rats in each group, and then used DEXA bone densitometer to scan the newborn callus BMD at the fracture site and record the data. The callus was located at the center of 1 cm from near to far. Each group was measured three times. Before each measure, the specimens were reset. The average value of.2.3 histology and immuno chemical examination was 1,2,3,4,5 weeks after the operation. 5 rats were randomly selected from each group. Under the anesthetic state, the bone fracture end was taken as the center, and half of the upper and lower 0.5cm specimens were cut. Half After being taken out, stored in liquid nitrogen (for fluorescence quantitative RT-PCR detection), half immediately placed in 10% formalin and fixed for 24 hours, 10%ED'A decalcified. After the embedding, the paraffin slice machine cut the bone tissue into 5 mu m slices. Routine pathological section was made and the immunohistochemical detection was used to analyze the.Leica-QwinV3 image analysis software according to the instructions. Changes in the gray value of TGF- beta 1 and BMP-2 were detected by.2.4 fluorescence quantitative RT-PCR. After extraction of 5 tibial callus samples in each group, the fluorescence quantitative RT-PCR detection.QRT-PCR was carried out by SYBR green PCR kit, without the template and the reverse transcription reactant as negative control. The PCR program was set with GAPDH as the internal parameter of RT-PCR. The fluorescent quantitative PC was set. R was used to detect the related data and analyze the results. 1. after hUCMSCs. inoculation was used to effectively isolate and purify 24 inoculation, the morphology of the adherent cells was long shuttle type, polygon or fibroblast like form, the size of the cells was uniform, and the whirl grew after 9 days. The flow cytometry was divided and the third generation cells highly expressed CD44, CD73, CD90 and CD105, low Expression of D14, CD34, CD45 and MHCI I. The alkaline phosphatase staining was strongly positive after osteogenesis, and alizarin red staining showed obvious calcium nodules. Oil red O staining showed that after injection of four oxalacil in the red.2. rats of the cytoplasm, most of them appeared polydipsia, polyuria, hyperglycemia, dull, loose skin and weight loss after 24-48 h. At present, the blood sugar was more than 16.7mmol/l, and the results of.3. bone density in the model of diabetes model showed that there was no significant statistical difference between the three groups of rat callus local bone mineral density (P0.05) at first weeks after the operation, but at week 2,3,4,5 after the operation, we found that the bone mineral density value of the callus in the diabetic rats was gradually increased with time, but at the corresponding time. The density value of the inter point was significantly lower than that of the control group. The difference of BMD in hUC-MSCs group was higher than that of the diabetic group at week 2,3,4,5 after the operation, the difference was significant (P0.05), but compared with the control group, the difference was not statistically significant (P0.05).4. histology and immunohistochemistry showed that the chondrocytes and osteogenesis of diabetic rats were fine. TGF- beta 1 and BMP-2 were widely expressed in the callus and periosteum at 1-3 weeks after the fracture, especially in the callus and periosteum, and the expression of the bone callus in the diabetic group was significantly lower than that in the.HUCMSCs group and the diabetic group of the normal group and the hUC-MSCs group,.5. BMP-2, TGF- beta 1 real-time fluorescent quantitative RT-PC. The R examination showed that the tissue BMP-2 in the normal group reached the peak at second weeks, while the diabetic group reached the peak in the third week, and the TGF- beta 1 at the broken end of the normal group reached the peak in third weeks, and the diabetes group reached the peak in the fourth week, and the TGF- beta 1 BMP-2 expression in the diabetic group was 1 weeks late than that in the normal control group, and BMP-2? TGF- beta 1 was expressed in the hUC-MSCs group in the hUC-MSCs group. 2,3 weeks were higher than those in the diabetic group, but there was little difference compared with those in the normal control group. Conclusion: 1. the human umbilical cord mesenchymal stem cells can be obtained by enzyme digestion in vitro. Human umbilical cord mesenchymal stem cells have multiple differentiation ability and can differentiate into osteoblasts and adipocytes.2. diabetic rats with slow healing speed and delayed healing of.3. Diabetes reduces the bone scab bone density at the fracture site, affects the formation of.4. diabetes in the fracture site and significantly reduces the expression of TGVF- beta 1, BMP-2, and then affects the formation of callus in the fracture of the rat, which is one of the reasons for the poor healing of the fracture. After the treatment of.5. application human umbilical cord mesenchymal stem cells, the expression of BMP-2 and TGF- beta 1 in the callus of the diabetic rats is increased. The increase of bone mineral density may be one of the molecular mechanisms of stem cell therapy to improve fracture healing. It can provide theoretical support for clinical treatment of diabetic fractures.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R587.2;R683

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