骨髓基质干细胞治疗淋巴水肿和RA-PTAS对血压、肾功能影响的研究
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摘要
第一部分：骨髓基质干细胞治疗淋巴水肿的实验研究
背景：
淋巴水肿(Lymphedema)是指机体的某些部位,由于淋巴引流障碍而引起组织和器官的肿胀。1983年,国际淋巴学会主席Casley-Smith JR估计,全世界大约有1亿4千万人患有各种类型的淋巴水肿,其中大约有四千五百万是肢体的淋巴水肿,并且人数越来越多。遗憾的是,目前从国内到国际淋巴水肿的研究没有引起医学界的重视,WHO也没有发布权威的专门的淋巴水肿性疾病的发病人数统计、分布、治疗等方面的数据,相对于其他疾病的研究,严重滞后。然而我们仍然可以从其它方面获得一些此类疾病的相关情况。
1994年以前,我国淋巴水肿的病人主要为丝虫病所致象皮肿病人,1994年我国终于实现了“全国基本上消除了丝虫病流行”。此时我国没有此病的权威统计资料,据多年从事淋巴回流障碍性疾病治疗和研究的中国工程院张涤生院士估计,全国象皮肿的病人数在500万以上。另外,乳癌术后继发上肢淋巴水肿需外科治疗的病人每年新增至少1万人。现在我国淋巴水肿的发病率越来越高,从乳腺癌术后淋巴水肿的情况,便可推知一二。
据世界卫生组织国际癌症研究中心发布的GLOBOCAN2008报道,中国2003-2007年全国32个肿瘤登记点的数据显示中国乳腺癌发病率为29.18/10万,每年中国乳腺癌新发病例数约为38万人。据2008年的数据显示乳腺癌手术后,有4%-56%的患者会发生患侧上肢的淋巴水肿。据此估计我国仅乳癌术后淋巴水肿病人每年新增1.5-21万人。由此可见,我国每年新增各种类型的淋巴水肿病例数将远超过1.5-21万人次。
迄今为止,在淋巴水肿的治疗方面尚无理想措施,国内外在临床上治疗淋巴水肿的方法主要是各种手术方法、物理按摩、电热和微波、苯吡喃酮药物治疗等方法,但这些方法均不理想,效果短暂、复发率高或者并发症多,都不能从根本上治愈淋巴水肿。这些淋巴水肿的病人每天忍受着肢体肿胀带来的生活和心理的双重折磨,因为组织间隙内蛋白的积聚,更易发生淋巴管炎和肢体的溃烂,使病人苦不堪言。
骨髓基质干细胞(Bone Marrow Stromal Cells, BMSCs)是成体骨髓细胞中,除造血干细胞之外的另一类骨髓干细胞,是多能或全能干细胞,来源于中胚层的间充质,属成体干细胞。1968年,Friendenstein等首次从骨髓中分离出。可在特定的体内为微环境下,能够诱导分化为多种组织细胞,其主要优点有：1.骨髓基质干细胞具有强大的增殖能力和多向分化潜能；2.骨髓基质干细胞易于分离、培养、扩增、纯化,不存在免疫排斥的特点,多次传代扩增和冷冻保存后仍具有干细胞特性；3.骨髓基质干细胞为成体干细胞,在应用方面涉及较少的伦理问题；4.可以转染外源基因并稳定高效表达。因此,骨髓基质干细胞在组织器官再生研究,组织器官老化和功能衰退,先天性或者遗传性疾病等方面均有广阔的发展空间,是目前公认的最理想的细胞治疗和基因治疗工具。
1996年,VEGF-C (vascular endothelial growth factor C)被瑞典的Joukov等人首次分离出,他们从前列腺癌的细胞中克隆了VEGF-C的cDNA。它的基因定位在人染色体4q34上,分子量约为46.9KD。Joukov等研究认为它是VEGF家族的成员,并命名为VEGF-C,同时提出了VEGF-C的受体为FLT-4(即VEGFR-3)。VEGF-C的信使RNA几乎在整个人体的组织中表达,包括胚胎。成体组织中,心脏,胎盘,卵巢癌和小肠的VEGF-C是高表达的。从1996年开始,VEGF-C的研究进度飞快,使其得到了深入的研究。有很多研究资料证明并阐述了它的基因构成,而且转录表达后其产物的微观结构以及生物学功能等也已经有很多报道。目前,此研究的热点还集中于受体、表达调节等方面,同时随着研究的深入,研究者发现VEGF-C与淋巴管内皮标志物的表达有很紧密的联系,它能够促进淋巴管内皮细胞的增生,调节其生物学活性。众多关于其受体的研究发现,VEGF-C的受体为VEGFR-2、VEGFR-3。它与VEGFR-2结合激活后,能够促进血管新生；当它与其另外一种受体-VEGFR-3结合激活后,能够促进淋巴管新生。大鼠VEGF-C152S是一点突变型VEGF-C,其第二个保守的半胱氨酸残基被丝氨酸残基所替代,与人的VEGF-C156S突变体相似,与野生型VEGF-C相比,它只能结合VEGFR-3,无法结合VEGFR-2,从而达到只促进淋巴管增生的目的。
骨髓基质干细胞在淋巴水肿的治疗方面,以及在干细胞向淋巴管内皮细胞诱导方面尚处于起始阶段。因此,为了获得VEGF-C152s在大鼠淋巴管内皮细胞的调节作用和在淋巴管生成作用中的有关线索,我们利用重组的大鼠VEGF-C152S诱导大鼠骨髓基质干细胞,并通过RT-PCR、免疫印迹法及免疫荧光技术,来观察VEGF-C152S诱导大鼠骨髓基质干细胞分化为淋巴管内皮细胞的情况,然后利用大鼠后肢环形切除部分皮肤并清扫深部淋巴管和淋巴结构建大鼠继发性淋巴水肿模型,并将经VEGF-C152S诱导分化后的骨髓基质干细胞移植入模型中,观察其治疗效果,为淋巴水肿性疾病的研究提供新的思路,以及理论和实验基础。
目的：
本实验旨在探讨VEGF-C152S诱导大鼠骨髓基质干细胞分化为淋巴管内皮细胞的情况,以及骨髓基质干细胞对大鼠淋巴水肿模型的治疗作用及对淋巴管新生的作用。为淋巴水肿性疾病的研究提供新的思路,以及理论和实验基础。
方法：
1、体外获取、分离、培养、扩增、鉴定大鼠骨髓基质干细胞。
2、取第三到五代细胞,利用重组的大鼠VEGF-A和VEGF-C152S在体外诱导分化大鼠骨髓基质干细胞,并通过RT-PCR.免疫印迹法及免疫荧光技术,观察确定大鼠骨髓基质干细胞是否表达淋巴管内皮细胞特异性的标志物Prox-1和LYVE-1,以及血管内皮细胞标志物CD34和CD31,来观察VEGF-A和VEGF-C152S诱导大鼠骨髓基质干细胞分化为淋巴管内皮细胞的可能性。
3、制作大鼠继发性淋巴水肿模型,将VEGF-C152S诱导后的骨髓基质干细胞注射到模型大鼠手术处的皮下组织,用测量水肿体积、B超、免疫荧光等方法检测,观察对淋巴水肿的治疗作用。
结果：
1、体外利用贴壁培养法成功培养、扩增了大鼠骨髓基质干细胞,并用流式细胞术检测了细胞表型及经不同方向的诱导分化,证实培养的细胞是大鼠骨髓基质干细胞。
2、应用大鼠VEGF-A与重组大鼠VEGF-C152S体外环境下,诱导大鼠骨髓基质干细胞,应用免疫荧光标记染色、Western Blot、RT-PCR等方法证实诱导后的细胞表达了淋巴管内皮标志物Prox-1和LYVE-1,而没有表达血管内皮标志物CD31和CD34。
3、在以往制作淋巴水肿模型的基础上,我们创新出了“肌肉皮肤离断缝合后二次手术环切法”来制作大鼠肢体淋巴水肿模型,成模率较高。在此模型上我们应用经大鼠重组VEGF-C152S诱导分化后的大鼠骨髓基质干细胞进行移植治疗,发现淋巴管新生增加,并可以明显缓解模型动物肢体淋巴水肿,说明其对大鼠淋巴水肿模型有治疗作用。
结论：
1、利用贴壁培养法获得骨髓基质干细胞的方法是可行的；应用大鼠VEGF-A与重组大鼠VEGF-C152S体外环境下,可以诱导大鼠骨髓基质干细胞淋巴管内皮细胞。
2、我们应用创新出的“肌肉皮肤离断缝合后二次手术环切法”来制作大鼠肢体淋巴水肿模型,效果可靠、成模率较高。
3、在大鼠肢体淋巴水肿模型上,我们应用经大鼠重组VEGF-C152S诱导分化后的大鼠骨髓基质干细胞进行移植治疗,发现淋巴管新生增加,并可以明显缓解模型动物肢体淋巴水肿,说明其对大鼠淋巴水肿模型有治疗作用。并且其治疗效果与细胞移植量有关,5×10^6个/每次与1×10^6/每次的剂量均有效,但是5×10^6个/每次的剂量效果更明显。
创新点：
1、根据我们诱导细胞分化的结果,我们首次提出了VEGF-A促进淋巴管新生的机制的假设,就是其通过VEGFR-2信号通路,促进了VEGFR-2高表达从而引起了Prox-1的表达上调,从而引起了细胞表达淋巴管内皮标志物。此研究可以为治疗淋巴管缺陷性疾病和抑制肿瘤淋巴管新生方面的研究,提供新的思路和理论支持。
2、我们创新出了“肌肉皮肤离断缝合后二次手术环切法”应用于制作大鼠肢体淋巴水肿模型,此法造模的成功率较高为68.1%,效果可靠。
3、首次应用经大鼠重组VEGF-C152S诱导分化后的大鼠骨髓基质干细胞,进行移植治疗,发现淋巴管新生增加,并可以明显缓解模型动物肢体淋巴水肿,说明其对大鼠淋巴水肿模型有治疗作用。其治疗效果与细胞移植量有关,5×10^6个/每次的剂量与1×10^6/每次的剂量均有效,但是5×10^6个/每次的剂量效果更明显。为人类继发性淋巴水肿的治疗提供了新的思路和实验基础。
第二部分：RA-PTAS对血压、肾功能影响的研究
背景：
肾动脉狭窄(RAS)被认为是继发性高血压的最常见的原因之一,多种因素可以导致肾动脉狭窄,如动脉粥样硬化,大动脉炎,肌纤维发育不良,支架内再狭窄等。肾动脉狭窄继续发展可引起肾血管性高血压和缺血性肾病,经常导致终末期肾功能衰竭,并增加心血管疾病的发病率和死亡率。由于肾动脉性高血压,有时口服降压药物没有反应。相比传统的手术方法,最近血管内介入治疗被作为治疗的肾动脉狭窄的主要手段,行经皮肾动脉成形术或支架植入术(Percutaneous renal artery angioplasty and/or stenting, RA-PTAS),以防止慢性肾功能不全。然而,此法是否能有效地控制血压,改善肾功能仍存在争议。目前,还没有明确的证据表明,这种方法可以防止肾功能逐渐恶化。
经皮肾动脉成形术或支架植入术与经典的手术方法相比,因为它的微创和较高的技术成功率,目前使用较多,但对于其预后,仍没有确切可靠的结论。在这项研究中,我们对115例行血管内介入治疗的患者进行回顾性分析,评价PTA治疗RAS的安全性和有效性。
目的：
评价血管内介入治疗术后肾动脉狭窄(RAS)的高血压患者的血压控制和肾功能的临床效果。
方法：
2004年1月至2011年12月,115名高血压患者共120条肾动脉,对手术前、后的血压和肾小球滤过率(GFR)进行了监测。术后口服抗血小板和抗高血压药物治疗。所有患者术后随访至少6个月。
结果：
110例患者成功地进行球囊血管成形术,并放置了94例肾动脉支架。高血压治愈19例,减轻61例。血压平稳26例,恶化9例。肾功能改善23例,肾功能稳定57例。肾功能恶化患者11例患者。出院6个月后多普勒超声检查,显示有87例病人肾动脉通畅。
结论：
经皮肾动脉成形术或支架植入术是有效和安全的,可以帮助控制血压,改善肾功能。
创新点：
我们的研究表明,对于高血压病人伴有肾动脉狭窄,应该进行积极的介入治疗,有助于控制血压和维持肾功能。
Part Ⅰ:Study of Bone Marrow Stromal Cells to Treat Lymphedema Background:
Lymphedema refers to certain parts of the body, caused by the swelling of the tissues and organs of the lymphatic drainage barriers. In1983, the International Society of lymphatic President Casley-Smith JR is estimated that there are about140million people worldwide suffer from various types of lymphedema, which is about45million limb lymphedema, and the number is increasing. Unfortunately, the lymphedema from domestic to international research did not arouse the attention of the medical profession, WHO has not released the number of authoritative specialized lymphedema disease incidence statistics, data distribution, treatment, relative to other diseases study. However, we can be obtained some information from other diseases.
Before1994, China's lymphedema patients with elephantiasis is caused by filariasis. Zhang Disheng,is an Academy of Chinese Engineering Academy, say that the National elephantiasis of the number of patients is more than five million. In addition, upper extremity lymphedema patients required surgical treatment caused by breast cancer surgery is increasing of at least10,000people.
According to the World Health Organization International Cancer Research Center released GLOBOCAN2008,2003-2007,32tumor registries point's data show that Chinese breast cancer incidence is29.18/10million, new cases is about38million people. According to the2008data show that4%-56%of patients occurred upper limb lymphedema. So only the number of breast cancer lymphedema patients is increasing of15-210thousand.
So far, there is no good method for the treatment of lymphedema. in the clinical, still use surgical, physical massage, electric and microwave, drugs treatment, but these methods are not satisfactory, the effect is short-lived, high recurrence rate or complications, it can not cure lymphedema.
Bone marrow stromal cells is the adult bone marrow cells, except hematopoietic stem cells, and more able or totipotent stem cells, derived from the mesoderm. In1968, Friendenstein first isolated it from the bone marrow. Specific in vivo microenvironment induced differentiation of a variety of tissue cells, its main advantage is:1. Marrow stromal cells has a strong proliferation capacity and multi-directional differentiation potential;2. easy separation, training, amplification, purification, there is no immune rejection characteristics, repeatedly passaged amplification and after cryopreservation still has the characteristics of stem cells;3. fewer ethical issues;4. can transfer exogenous gene and efficient and stable expression. Therefore, have broad space for development in the study of regeneration of tissues and organs.
In1996, vascular endothelial growth factor C, Swedish Joukov et al isolated it for the first time. Its gene is located on human chromosome4q34, molecular weight about46.9KD. Joukov and other studies suggest that it is a member of the VEGF family, and named the VEGF-C, VEGF-C receptor FLT-4(VEGFR-3). Messenger RNA of the VEGF-C is expressed in almost the entire human tissue, including embryonic. Into the body tissue in the heart, placenta, ovarian cancer, and small intestine of VEGF-C is highly expressed. The progress of the study of the VEGF-C is fast. Many studies have documented and elaborated its genetic makeup, the microscopic structure of the product as well as the biological function and transcriptional expression has also been a lot of reports. Currently hot research also focused on receptor expression regulation, etc. With further research, the researchers found that the expression of VEGF-C and lymphatic endothelial marker very closely linked to its ability to promote lymphatic endothelial cell proliferation, regulating its biological activity. Many studies show that it has two receptors, VEGFR-2and VEGFR-3. Combination with VEGFR-2can induce angiogenesis, combined with VEGFR-3can promote lymphangiogenesis. VEGF-C152S is a point mutant generated by the replacement of the second conserved Cys residue of the recombinant processed VEGF-C by a Ser residue. VEGF-C152S is analog to the human VEGF-C156S mutant and only active toward VEGFR-3/FLT-4but, unlike wild type VEGF-C, is unable to bind to and to activate signaling through VEGFR-2/KDR.
Bone marrow stromal cells in the treatment of lymphedema is still in the initial stage, therefore, in order to obtain the VEGF-C152S how to regulation of rat lymphatic endothelial cells and lymphangiogenesis, using VEGF-C152S to induce bone marrow stromal cells. And use RT-PCR, Western blot and immunofluorescence techniques to observe. And then use removing a part of the skin and clean the deep lymphatic vessels and lymph nodes to make a secondary lymphedema model, and transplanted BMSCs into the model, observed treatment effect.
Objective:
This study was designed to investigate VEGF-C152S induced bone marrow stromal cells into the lymphatic endothelial cells, and the treatment to lymphedema.
Methods:
1. Obtain, separate, culture, amplify, and identify the rat bone marrow stromal cells in vitro.
2. Take the third to five generations of cells using recombinant rat VEGF-A and VEGF-C152S in vitro to differentiate the rat bone marrow stromal cells, and determine the cells using RT-PCR, Western blot and immunofluorescence techniques, stem cells express the lymphatic endothelial cell-specific flag material Prox-1and LYVE-1, as well as vascular endothelial cell markers of CD34and of CD31, to observe the VEGF-A and of VEGF-C152S induced rat bone marrow stromal cell differentiate to the lymphatic vessels.
3. Make the rat secondary lymphedema model, VEGF-C152S-induced bone marrow stromal cells were injected into the subcutaneous tissue of the rat model, to observe the therapeutic effect of lymphedema.
Results:
1. Obtain, separate, culture and identify the rat bone marrow stromal cells in vitro successfully
2. Using recombinant rat VEGF-A and VEGF-C152S in vitro to differentiate the rat bone marrow stromal cells, and determine the cells using RT-PCR, Western blot and immunofluorescence techniques, we find that stromal cells express the lymphatic endothelial cell-specific flag material Prox-1and LYVE-1, do not express vascular endothelial cell markers of CD34and of CD31, we observed that the VEGF-A and of VEGF-C152S induced rat bone marrow stromal cell differentiate to the lymphatic vessels.
3. We use an new method to make the lymphedema model based on the old method, it has a higher rate. We use the rat recombinant VEGF-C152S-induced rat bone marrow stromal stem cells to transplant in the model and found that it can increase lymphangiogenesis, and can treat lymphedema.
Conclusion:
1. The method is feasible to obtain, separate, culture, amplify the rat bone marrow stromal cells in vitro, using recombinant rat VEGF-A and VEGF-C152S can differentiate the rat bone marrow stromal cells towards lymphatic endothelial cell in vitro.
2. Our new mehod "Circumcision after the surgery of cut the muscle and skin" create a good model of rat limb lymphedema, it has a higher rate.
3. In rat limb lymphedema model, we use the rat recombinant VEGF-C152S-induced rat bone marrow stromal stem cells to transplant and found that it can increase lymphangiogenesis, and can treat lymphedema. And its therapeutic effect is related to the amount of cells, both5×10Λ6/per dose and1×10Λ6/per dose has effection,5×10Λ6/per dose is more pronounced.
Bring New Ideas:
1. According to our results induce cell differentiation, we first proposed the mechanism of VEGF-A to promote lymphangiogenesis is that it through the VEGFR-2signaling pathway to promote VEGFR-2high expression and cause Prox-1 upregulated, and then cause the cells express lymphatic endothelial cells markers. This study can provide new ideas and theoretical support for inhibiting tumor lymphangiogenesis and the treatment of lymphatic deficiency diseases.
2. Our new mehod "Circumcision after the surgery of cut the muscle and skin" create a good model of rat limb lymphedema, it has a higher rate.
3. We use the rat recombinant VEGF-C152S-induced rat bone marrow stromal stem cells to transplant it in rat limb lymphedema model and found that it can increase lymphangiogenesis for the first time,and find it can treat lymphedema. And its therapeutic effect is related to the amount of cells, both5×10Λ6/per dose and1×10Λ6/per dose has effection,5×10Λ6/per dose is more pronounced. all of those provide new ideas and experimental work for the treatment of human secondary lymphedema.
Part Ⅱ:The Effect of Percutaneous Renal Artery Angioplasty and/or Stenting (RA-PTAS) on Blood Pressure and Kidney Function Background:
Renal artery stenosis (RAS) can cause renovascular hypertension and ischemic nephropathy, frequently resulting in end-stage renal failure. Several studies reported increased prevalence of ischemic nephropathy with special reference to renal artery stenosis due to atherosclerosis in elderly patients. Hypertension due to RAS is sometimes not responsive to oral antihypertensive drugs. Instead of the traditional surgical approach, endovascular treatment has recently been accepted as the primary line of treatment of renal artery stenosis to revascularize the stenotic artery and prevent chronic renal insufficiency. However, whether this procedure can effectively controlling blood pressure and improve renal function remains controversial. Currently, there is no clear evidence that this procedure can prevent progressive deterioration of renal function.
Nevertheless, there are patients with satisfactory outcomes in terms of improvement or stabilization of renal function. while a portion of patients may have deteriorated renal function after balloon angioplasty and stent deployment. In this study, we report on endovascular treatment of115patients with RAS who underwent endovascular treatment and evaluate the safety and efficacy of this procedure. Our experience confirm the efficacy of this procedure and provide helpful experiences for clinicians.
Objective:
To evaluate the clinical effect of endovascular treatment on postoperative blood pressure control and kidney function of hypertensive patients with renal artery stenosis (RAS).
Methods:
Between January2004and December2011, RAS was diagnosed in120renal arteries from115hypertensive patients. Pre-and post-operative blood pressure and glomerular filtration rate (GFR) were monitored. Postoperative oral antiplatelet and antihypertensive agents were administered. Clinical follow-up was available for all patients for at least6months.
Results:
Balloon angioplasty was performed successfully in110patients, and stents were deployed in94renal arteries from89patients. Hypertension was cured or lessened in19and61patients, respectively. Blood pressure was stable and worsened in26and9patients, respectively. The renal function improved and was stable in23patients and57patients, respectively. Deterioration of renal function was observed in11patients. Doppler ultrasound after discharge revealed87patent renal arteries and fixed stents in82patients6months after procedure.
Conclusion:
Balloon angioplasty and stent deployment is an effective and feasible procedure for patients with RAS that help in controlling blood pressure and improving renal function moderately.
Bring New Ideas:
Balloon angioplasty and stent deployment is an effective and feasible procedure for patients with RAS that help in controlling blood pressure and improving renal function.
背景：
淋巴水肿(Lymphedema)是指机体的某些部位,由于淋巴引流障碍而引起组织和器官的肿胀。1983年,国际淋巴学会主席Casley-Smith JR估计,全世界大约有1亿4千万人患有各种类型的淋巴水肿,其中大约有四千五百万是肢体的淋巴水肿,并且人数越来越多。遗憾的是,目前从国内到国际淋巴水肿的研究没有引起医学界的重视,WHO也没有发布权威的专门的淋巴水肿性疾病的发病人数统计、分布、治疗等方面的数据,相对于其他疾病的研究,严重滞后。然而我们仍然可以从其它方面获得一些此类疾病的相关情况。
1994年以前,我国淋巴水肿的病人主要为丝虫病所致象皮肿病人,1994年我国终于实现了“全国基本上消除了丝虫病流行”。此时我国没有此病的权威统计资料,据多年从事淋巴回流障碍性疾病治疗和研究的中国工程院张涤生院士估计,全国象皮肿的病人数在500万以上。另外,乳癌术后继发上肢淋巴水肿需外科治疗的病人每年新增至少1万人。现在我国淋巴水肿的发病率越来越高,从乳腺癌术后淋巴水肿的情况,便可推知一二。
据世界卫生组织国际癌症研究中心发布的GLOBOCAN2008报道,中国2003-2007年全国32个肿瘤登记点的数据显示中国乳腺癌发病率为29.18/10万,每年中国乳腺癌新发病例数约为38万人。据2008年的数据显示乳腺癌手术后,有4%-56%的患者会发生患侧上肢的淋巴水肿。据此估计我国仅乳癌术后淋巴水肿病人每年新增1.5-21万人。由此可见,我国每年新增各种类型的淋巴水肿病例数将远超过1.5-21万人次。
迄今为止,在淋巴水肿的治疗方面尚无理想措施,国内外在临床上治疗淋巴水肿的方法主要是各种手术方法、物理按摩、电热和微波、苯吡喃酮药物治疗等方法,但这些方法均不理想,效果短暂、复发率高或者并发症多,都不能从根本上治愈淋巴水肿。这些淋巴水肿的病人每天忍受着肢体肿胀带来的生活和心理的双重折磨,因为组织间隙内蛋白的积聚,更易发生淋巴管炎和肢体的溃烂,使病人苦不堪言。
骨髓基质干细胞(Bone Marrow Stromal Cells, BMSCs)是成体骨髓细胞中,除造血干细胞之外的另一类骨髓干细胞,是多能或全能干细胞,来源于中胚层的间充质,属成体干细胞。1968年,Friendenstein等首次从骨髓中分离出。可在特定的体内为微环境下,能够诱导分化为多种组织细胞,其主要优点有：1.骨髓基质干细胞具有强大的增殖能力和多向分化潜能；2.骨髓基质干细胞易于分离、培养、扩增、纯化,不存在免疫排斥的特点,多次传代扩增和冷冻保存后仍具有干细胞特性；3.骨髓基质干细胞为成体干细胞,在应用方面涉及较少的伦理问题；4.可以转染外源基因并稳定高效表达。因此,骨髓基质干细胞在组织器官再生研究,组织器官老化和功能衰退,先天性或者遗传性疾病等方面均有广阔的发展空间,是目前公认的最理想的细胞治疗和基因治疗工具。
1996年,VEGF-C (vascular endothelial growth factor C)被瑞典的Joukov等人首次分离出,他们从前列腺癌的细胞中克隆了VEGF-C的cDNA。它的基因定位在人染色体4q34上,分子量约为46.9KD。Joukov等研究认为它是VEGF家族的成员,并命名为VEGF-C,同时提出了VEGF-C的受体为FLT-4(即VEGFR-3)。VEGF-C的信使RNA几乎在整个人体的组织中表达,包括胚胎。成体组织中,心脏,胎盘,卵巢癌和小肠的VEGF-C是高表达的。从1996年开始,VEGF-C的研究进度飞快,使其得到了深入的研究。有很多研究资料证明并阐述了它的基因构成,而且转录表达后其产物的微观结构以及生物学功能等也已经有很多报道。目前,此研究的热点还集中于受体、表达调节等方面,同时随着研究的深入,研究者发现VEGF-C与淋巴管内皮标志物的表达有很紧密的联系,它能够促进淋巴管内皮细胞的增生,调节其生物学活性。众多关于其受体的研究发现,VEGF-C的受体为VEGFR-2、VEGFR-3。它与VEGFR-2结合激活后,能够促进血管新生；当它与其另外一种受体-VEGFR-3结合激活后,能够促进淋巴管新生。大鼠VEGF-C152S是一点突变型VEGF-C,其第二个保守的半胱氨酸残基被丝氨酸残基所替代,与人的VEGF-C156S突变体相似,与野生型VEGF-C相比,它只能结合VEGFR-3,无法结合VEGFR-2,从而达到只促进淋巴管增生的目的。
骨髓基质干细胞在淋巴水肿的治疗方面,以及在干细胞向淋巴管内皮细胞诱导方面尚处于起始阶段。因此,为了获得VEGF-C152s在大鼠淋巴管内皮细胞的调节作用和在淋巴管生成作用中的有关线索,我们利用重组的大鼠VEGF-C152S诱导大鼠骨髓基质干细胞,并通过RT-PCR、免疫印迹法及免疫荧光技术,来观察VEGF-C152S诱导大鼠骨髓基质干细胞分化为淋巴管内皮细胞的情况,然后利用大鼠后肢环形切除部分皮肤并清扫深部淋巴管和淋巴结构建大鼠继发性淋巴水肿模型,并将经VEGF-C152S诱导分化后的骨髓基质干细胞移植入模型中,观察其治疗效果,为淋巴水肿性疾病的研究提供新的思路,以及理论和实验基础。
目的：
本实验旨在探讨VEGF-C152S诱导大鼠骨髓基质干细胞分化为淋巴管内皮细胞的情况,以及骨髓基质干细胞对大鼠淋巴水肿模型的治疗作用及对淋巴管新生的作用。为淋巴水肿性疾病的研究提供新的思路,以及理论和实验基础。
方法：
1、体外获取、分离、培养、扩增、鉴定大鼠骨髓基质干细胞。
2、取第三到五代细胞,利用重组的大鼠VEGF-A和VEGF-C152S在体外诱导分化大鼠骨髓基质干细胞,并通过RT-PCR.免疫印迹法及免疫荧光技术,观察确定大鼠骨髓基质干细胞是否表达淋巴管内皮细胞特异性的标志物Prox-1和LYVE-1,以及血管内皮细胞标志物CD34和CD31,来观察VEGF-A和VEGF-C152S诱导大鼠骨髓基质干细胞分化为淋巴管内皮细胞的可能性。
3、制作大鼠继发性淋巴水肿模型,将VEGF-C152S诱导后的骨髓基质干细胞注射到模型大鼠手术处的皮下组织,用测量水肿体积、B超、免疫荧光等方法检测,观察对淋巴水肿的治疗作用。
结果：
1、体外利用贴壁培养法成功培养、扩增了大鼠骨髓基质干细胞,并用流式细胞术检测了细胞表型及经不同方向的诱导分化,证实培养的细胞是大鼠骨髓基质干细胞。
2、应用大鼠VEGF-A与重组大鼠VEGF-C152S体外环境下,诱导大鼠骨髓基质干细胞,应用免疫荧光标记染色、Western Blot、RT-PCR等方法证实诱导后的细胞表达了淋巴管内皮标志物Prox-1和LYVE-1,而没有表达血管内皮标志物CD31和CD34。
3、在以往制作淋巴水肿模型的基础上,我们创新出了“肌肉皮肤离断缝合后二次手术环切法”来制作大鼠肢体淋巴水肿模型,成模率较高。在此模型上我们应用经大鼠重组VEGF-C152S诱导分化后的大鼠骨髓基质干细胞进行移植治疗,发现淋巴管新生增加,并可以明显缓解模型动物肢体淋巴水肿,说明其对大鼠淋巴水肿模型有治疗作用。
结论：
1、利用贴壁培养法获得骨髓基质干细胞的方法是可行的；应用大鼠VEGF-A与重组大鼠VEGF-C152S体外环境下,可以诱导大鼠骨髓基质干细胞淋巴管内皮细胞。
2、我们应用创新出的“肌肉皮肤离断缝合后二次手术环切法”来制作大鼠肢体淋巴水肿模型,效果可靠、成模率较高。
3、在大鼠肢体淋巴水肿模型上,我们应用经大鼠重组VEGF-C152S诱导分化后的大鼠骨髓基质干细胞进行移植治疗,发现淋巴管新生增加,并可以明显缓解模型动物肢体淋巴水肿,说明其对大鼠淋巴水肿模型有治疗作用。并且其治疗效果与细胞移植量有关,5×10^6个/每次与1×10^6/每次的剂量均有效,但是5×10^6个/每次的剂量效果更明显。
创新点：
1、根据我们诱导细胞分化的结果,我们首次提出了VEGF-A促进淋巴管新生的机制的假设,就是其通过VEGFR-2信号通路,促进了VEGFR-2高表达从而引起了Prox-1的表达上调,从而引起了细胞表达淋巴管内皮标志物。此研究可以为治疗淋巴管缺陷性疾病和抑制肿瘤淋巴管新生方面的研究,提供新的思路和理论支持。
2、我们创新出了“肌肉皮肤离断缝合后二次手术环切法”应用于制作大鼠肢体淋巴水肿模型,此法造模的成功率较高为68.1%,效果可靠。
3、首次应用经大鼠重组VEGF-C152S诱导分化后的大鼠骨髓基质干细胞,进行移植治疗,发现淋巴管新生增加,并可以明显缓解模型动物肢体淋巴水肿,说明其对大鼠淋巴水肿模型有治疗作用。其治疗效果与细胞移植量有关,5×10^6个/每次的剂量与1×10^6/每次的剂量均有效,但是5×10^6个/每次的剂量效果更明显。为人类继发性淋巴水肿的治疗提供了新的思路和实验基础。
第二部分：RA-PTAS对血压、肾功能影响的研究
背景：
肾动脉狭窄(RAS)被认为是继发性高血压的最常见的原因之一,多种因素可以导致肾动脉狭窄,如动脉粥样硬化,大动脉炎,肌纤维发育不良,支架内再狭窄等。肾动脉狭窄继续发展可引起肾血管性高血压和缺血性肾病,经常导致终末期肾功能衰竭,并增加心血管疾病的发病率和死亡率。由于肾动脉性高血压,有时口服降压药物没有反应。相比传统的手术方法,最近血管内介入治疗被作为治疗的肾动脉狭窄的主要手段,行经皮肾动脉成形术或支架植入术(Percutaneous renal artery angioplasty and/or stenting, RA-PTAS),以防止慢性肾功能不全。然而,此法是否能有效地控制血压,改善肾功能仍存在争议。目前,还没有明确的证据表明,这种方法可以防止肾功能逐渐恶化。
经皮肾动脉成形术或支架植入术与经典的手术方法相比,因为它的微创和较高的技术成功率,目前使用较多,但对于其预后,仍没有确切可靠的结论。在这项研究中,我们对115例行血管内介入治疗的患者进行回顾性分析,评价PTA治疗RAS的安全性和有效性。
目的：
评价血管内介入治疗术后肾动脉狭窄(RAS)的高血压患者的血压控制和肾功能的临床效果。
方法：
2004年1月至2011年12月,115名高血压患者共120条肾动脉,对手术前、后的血压和肾小球滤过率(GFR)进行了监测。术后口服抗血小板和抗高血压药物治疗。所有患者术后随访至少6个月。
结果：
110例患者成功地进行球囊血管成形术,并放置了94例肾动脉支架。高血压治愈19例,减轻61例。血压平稳26例,恶化9例。肾功能改善23例,肾功能稳定57例。肾功能恶化患者11例患者。出院6个月后多普勒超声检查,显示有87例病人肾动脉通畅。
结论：
经皮肾动脉成形术或支架植入术是有效和安全的,可以帮助控制血压,改善肾功能。
创新点：
我们的研究表明,对于高血压病人伴有肾动脉狭窄,应该进行积极的介入治疗,有助于控制血压和维持肾功能。
Part Ⅰ:Study of Bone Marrow Stromal Cells to Treat Lymphedema Background:
Lymphedema refers to certain parts of the body, caused by the swelling of the tissues and organs of the lymphatic drainage barriers. In1983, the International Society of lymphatic President Casley-Smith JR is estimated that there are about140million people worldwide suffer from various types of lymphedema, which is about45million limb lymphedema, and the number is increasing. Unfortunately, the lymphedema from domestic to international research did not arouse the attention of the medical profession, WHO has not released the number of authoritative specialized lymphedema disease incidence statistics, data distribution, treatment, relative to other diseases study. However, we can be obtained some information from other diseases.
Before1994, China's lymphedema patients with elephantiasis is caused by filariasis. Zhang Disheng,is an Academy of Chinese Engineering Academy, say that the National elephantiasis of the number of patients is more than five million. In addition, upper extremity lymphedema patients required surgical treatment caused by breast cancer surgery is increasing of at least10,000people.
According to the World Health Organization International Cancer Research Center released GLOBOCAN2008,2003-2007,32tumor registries point's data show that Chinese breast cancer incidence is29.18/10million, new cases is about38million people. According to the2008data show that4%-56%of patients occurred upper limb lymphedema. So only the number of breast cancer lymphedema patients is increasing of15-210thousand.
So far, there is no good method for the treatment of lymphedema. in the clinical, still use surgical, physical massage, electric and microwave, drugs treatment, but these methods are not satisfactory, the effect is short-lived, high recurrence rate or complications, it can not cure lymphedema.
Bone marrow stromal cells is the adult bone marrow cells, except hematopoietic stem cells, and more able or totipotent stem cells, derived from the mesoderm. In1968, Friendenstein first isolated it from the bone marrow. Specific in vivo microenvironment induced differentiation of a variety of tissue cells, its main advantage is:1. Marrow stromal cells has a strong proliferation capacity and multi-directional differentiation potential;2. easy separation, training, amplification, purification, there is no immune rejection characteristics, repeatedly passaged amplification and after cryopreservation still has the characteristics of stem cells;3. fewer ethical issues;4. can transfer exogenous gene and efficient and stable expression. Therefore, have broad space for development in the study of regeneration of tissues and organs.
In1996, vascular endothelial growth factor C, Swedish Joukov et al isolated it for the first time. Its gene is located on human chromosome4q34, molecular weight about46.9KD. Joukov and other studies suggest that it is a member of the VEGF family, and named the VEGF-C, VEGF-C receptor FLT-4(VEGFR-3). Messenger RNA of the VEGF-C is expressed in almost the entire human tissue, including embryonic. Into the body tissue in the heart, placenta, ovarian cancer, and small intestine of VEGF-C is highly expressed. The progress of the study of the VEGF-C is fast. Many studies have documented and elaborated its genetic makeup, the microscopic structure of the product as well as the biological function and transcriptional expression has also been a lot of reports. Currently hot research also focused on receptor expression regulation, etc. With further research, the researchers found that the expression of VEGF-C and lymphatic endothelial marker very closely linked to its ability to promote lymphatic endothelial cell proliferation, regulating its biological activity. Many studies show that it has two receptors, VEGFR-2and VEGFR-3. Combination with VEGFR-2can induce angiogenesis, combined with VEGFR-3can promote lymphangiogenesis. VEGF-C152S is a point mutant generated by the replacement of the second conserved Cys residue of the recombinant processed VEGF-C by a Ser residue. VEGF-C152S is analog to the human VEGF-C156S mutant and only active toward VEGFR-3/FLT-4but, unlike wild type VEGF-C, is unable to bind to and to activate signaling through VEGFR-2/KDR.
Bone marrow stromal cells in the treatment of lymphedema is still in the initial stage, therefore, in order to obtain the VEGF-C152S how to regulation of rat lymphatic endothelial cells and lymphangiogenesis, using VEGF-C152S to induce bone marrow stromal cells. And use RT-PCR, Western blot and immunofluorescence techniques to observe. And then use removing a part of the skin and clean the deep lymphatic vessels and lymph nodes to make a secondary lymphedema model, and transplanted BMSCs into the model, observed treatment effect.
Objective:
This study was designed to investigate VEGF-C152S induced bone marrow stromal cells into the lymphatic endothelial cells, and the treatment to lymphedema.
Methods:
1. Obtain, separate, culture, amplify, and identify the rat bone marrow stromal cells in vitro.
2. Take the third to five generations of cells using recombinant rat VEGF-A and VEGF-C152S in vitro to differentiate the rat bone marrow stromal cells, and determine the cells using RT-PCR, Western blot and immunofluorescence techniques, stem cells express the lymphatic endothelial cell-specific flag material Prox-1and LYVE-1, as well as vascular endothelial cell markers of CD34and of CD31, to observe the VEGF-A and of VEGF-C152S induced rat bone marrow stromal cell differentiate to the lymphatic vessels.
3. Make the rat secondary lymphedema model, VEGF-C152S-induced bone marrow stromal cells were injected into the subcutaneous tissue of the rat model, to observe the therapeutic effect of lymphedema.
Results:
1. Obtain, separate, culture and identify the rat bone marrow stromal cells in vitro successfully
2. Using recombinant rat VEGF-A and VEGF-C152S in vitro to differentiate the rat bone marrow stromal cells, and determine the cells using RT-PCR, Western blot and immunofluorescence techniques, we find that stromal cells express the lymphatic endothelial cell-specific flag material Prox-1and LYVE-1, do not express vascular endothelial cell markers of CD34and of CD31, we observed that the VEGF-A and of VEGF-C152S induced rat bone marrow stromal cell differentiate to the lymphatic vessels.
3. We use an new method to make the lymphedema model based on the old method, it has a higher rate. We use the rat recombinant VEGF-C152S-induced rat bone marrow stromal stem cells to transplant in the model and found that it can increase lymphangiogenesis, and can treat lymphedema.
Conclusion:
1. The method is feasible to obtain, separate, culture, amplify the rat bone marrow stromal cells in vitro, using recombinant rat VEGF-A and VEGF-C152S can differentiate the rat bone marrow stromal cells towards lymphatic endothelial cell in vitro.
2. Our new mehod "Circumcision after the surgery of cut the muscle and skin" create a good model of rat limb lymphedema, it has a higher rate.
3. In rat limb lymphedema model, we use the rat recombinant VEGF-C152S-induced rat bone marrow stromal stem cells to transplant and found that it can increase lymphangiogenesis, and can treat lymphedema. And its therapeutic effect is related to the amount of cells, both5×10Λ6/per dose and1×10Λ6/per dose has effection,5×10Λ6/per dose is more pronounced.
Bring New Ideas:
1. According to our results induce cell differentiation, we first proposed the mechanism of VEGF-A to promote lymphangiogenesis is that it through the VEGFR-2signaling pathway to promote VEGFR-2high expression and cause Prox-1 upregulated, and then cause the cells express lymphatic endothelial cells markers. This study can provide new ideas and theoretical support for inhibiting tumor lymphangiogenesis and the treatment of lymphatic deficiency diseases.
2. Our new mehod "Circumcision after the surgery of cut the muscle and skin" create a good model of rat limb lymphedema, it has a higher rate.
3. We use the rat recombinant VEGF-C152S-induced rat bone marrow stromal stem cells to transplant it in rat limb lymphedema model and found that it can increase lymphangiogenesis for the first time,and find it can treat lymphedema. And its therapeutic effect is related to the amount of cells, both5×10Λ6/per dose and1×10Λ6/per dose has effection,5×10Λ6/per dose is more pronounced. all of those provide new ideas and experimental work for the treatment of human secondary lymphedema.
Part Ⅱ:The Effect of Percutaneous Renal Artery Angioplasty and/or Stenting (RA-PTAS) on Blood Pressure and Kidney Function Background:
Renal artery stenosis (RAS) can cause renovascular hypertension and ischemic nephropathy, frequently resulting in end-stage renal failure. Several studies reported increased prevalence of ischemic nephropathy with special reference to renal artery stenosis due to atherosclerosis in elderly patients. Hypertension due to RAS is sometimes not responsive to oral antihypertensive drugs. Instead of the traditional surgical approach, endovascular treatment has recently been accepted as the primary line of treatment of renal artery stenosis to revascularize the stenotic artery and prevent chronic renal insufficiency. However, whether this procedure can effectively controlling blood pressure and improve renal function remains controversial. Currently, there is no clear evidence that this procedure can prevent progressive deterioration of renal function.
Nevertheless, there are patients with satisfactory outcomes in terms of improvement or stabilization of renal function. while a portion of patients may have deteriorated renal function after balloon angioplasty and stent deployment. In this study, we report on endovascular treatment of115patients with RAS who underwent endovascular treatment and evaluate the safety and efficacy of this procedure. Our experience confirm the efficacy of this procedure and provide helpful experiences for clinicians.
Objective:
To evaluate the clinical effect of endovascular treatment on postoperative blood pressure control and kidney function of hypertensive patients with renal artery stenosis (RAS).
Methods:
Between January2004and December2011, RAS was diagnosed in120renal arteries from115hypertensive patients. Pre-and post-operative blood pressure and glomerular filtration rate (GFR) were monitored. Postoperative oral antiplatelet and antihypertensive agents were administered. Clinical follow-up was available for all patients for at least6months.
Results:
Balloon angioplasty was performed successfully in110patients, and stents were deployed in94renal arteries from89patients. Hypertension was cured or lessened in19and61patients, respectively. Blood pressure was stable and worsened in26and9patients, respectively. The renal function improved and was stable in23patients and57patients, respectively. Deterioration of renal function was observed in11patients. Doppler ultrasound after discharge revealed87patent renal arteries and fixed stents in82patients6months after procedure.
Conclusion:
Balloon angioplasty and stent deployment is an effective and feasible procedure for patients with RAS that help in controlling blood pressure and improving renal function moderately.
Bring New Ideas:
Balloon angioplasty and stent deployment is an effective and feasible procedure for patients with RAS that help in controlling blood pressure and improving renal function.
引文
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