Effect of stromal cell-derived factor-1/CXCR4 axis in neural stem cell transplantation for Parkinson’s disease

Previous studies have shown that neural stem cell transplantation has the potential to treat Parkinson’s disease,but its specific mechanism of action is still unclear.Stromal cell-derived factor-1 and its receptor,chemokine receptor 4(CXCR4),are important regulators of cell migration.We speculated that the CXCR4/stromal cell-derived factor 1 axis may be involved in the therapeutic effect of neural stem cell transplantation in the treatment of Parkinson’s disease.A Parkinson’s disease rat model was injected with 6-hydroxydopamine via the right ascending nigrostriatal dopaminergic pathway,and then treated with 5μL of neural stem cell suspension(1.5×104/L)in the right substantia nigra.Rats were intraperitoneally injected once daily for 3 days with 1.25 mL/kg of the CXCR4 antagonist AMD3100 to observe changes after neural stem cell transplantation.Parkinson-like behavior in rats was detected using apomorphine-induced rotation.Immunofluorescence staining was used to determine the immunoreactivity of tyrosine hydroxylase,CXCR4,and stromal cell-derived factor-1 in the brain.Using quantitative real-time polymerase chain reaction,the mRNA expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra were measured.In addition,western blot assays were performed to analyze the protein expression of stromal cell-derived factor-1 and CXCR4.Our results demonstrated that neural stem cell transplantation noticeably reduced apomorphine-induced rotation,increased the mRNA and protein expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra,and enhanced the immunoreactivity of tyrosine hydroxylase,CXCR4,and stromal cell-derived factor-1 in the brain.Injection of AMD3100 inhibited the aforementioned effects.These findings suggest that the stromal cell-derived factor-1/CXCR4 axis may play a significant role in the therapeutic effect of neural stem cell transplantation in a rat model of Parkinson’s disease.This study was approved by the Animal Care and Use Committee of Kunming Medical University,China(approval No.SYXKK2015-0002)on April 1,2014.     

A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8⁺ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα⁺ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.     

外泌体在肿瘤转移前微环境形成中的作用

肿瘤的转移前微环境（pre-metastatic niche，PMN）特指原发肿瘤灶为肿瘤细胞远处播散和定植准备的微环境，此微环境的六个特征包括炎症、免疫抑制、血管生成/血管通透性、亲器官性、重编程和淋巴管生成。PMN形成的关键成分包括肿瘤源性分泌因子、细胞外囊泡（含外泌体）、骨髓源性细胞、免疫抑制细胞和宿主基质细胞等，其中，外泌体作为细胞间重要的信使，在肿瘤PMN的形成中具有重要作用。本综述就外泌体在肿瘤PMN形成中的作用进行探讨。     

外泌体微RNA治疗骨关节炎研究进展

骨关节炎是骨科常见的顽固性疾病之一,因其高发病率、高致残率,给患者和社会带来沉重的负担。随着组织工程领域的飞速发展,外泌体治疗骨关节炎的潜力已得到证实。其中,外泌体特异性微RNA（miRNA）可抑制软骨降解和滑膜炎症、促进软骨下骨重塑,从而缓解甚至逆转骨关节炎的病理改变。本文对外泌体miRNA治疗对骨关节炎患者软骨、滑膜、软骨细胞外基质及软骨下骨的影响进行综述,以期为临床上应用外泌体miRNA治疗骨关节炎提供参考。     

尿源干细胞及其外泌体治疗肾脏病的作用北大核心

背景:尿源干细胞为尿液中存在的间充质干细胞,具备自我增殖与多向分化的潜能,由于其本身存在于泌尿系统,并且很可能来源于肾脏组织,相较于其他间充质干细胞存在先天的优势,因此尿源干细胞及其外泌体可能具备对于肾脏病的特殊干预作用。目的:综述尿源干细胞及其外泌体的生物学特性,以及二者在肾脏病领域的应用进展,以期为临床肾脏疾病的治疗提供新思路。方法:以“urine-derived stem cell*,urine-derived stromal cell*,urine-derived mesenchymal stem cell*,urine-derived mesenchymal stromal cell*,urine-derived progenitor cell*,kidney diseases,acute kidney injury,diabetic nephropathies,kidney failure,chronic,tissue engineering,organoids”为检索词检索PubMed数据库,以“尿源干细胞,急性肾损伤,慢性肾病,糖尿病肾病,组织工程,类器官”为检索词检索CNKI数据库,发表时间限定为2000年1月至2021年10月。检索后严格按照纳入和排除标准进行人为筛选,最终纳入31篇文献进行综述。结果与结论:①尿源干细胞作为泌尿系统来源的间充质干细胞,具备间充质干细胞共有的特性。此外,其在肾脏病领域是一种有效的干预措施和适宜的种子细胞来源;②尿源干细胞及其外泌体在急性肾损伤动物及细胞模型上,可以显著缓解肾功能损害和组织学损伤,抑制炎症、细胞凋亡和氧化应激;在慢性肾脏病(包括糖尿病肾病)方面,尿源干细胞及其外泌体可以延缓肾功能进展及组织学改变,抑制炎症细胞浸润及纤维化,发挥对足细胞的保护作用;此外,其在肾脏组织工程与再生医学领域的应用也同样具有广阔的前景;③虽然尿源干细胞及其外泌体在肾脏病领域的研究尚处于初始阶段,但已体现出较大的潜力和价值,在未来有望成为临床肾脏病治疗的有效手段之一。     

Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection

BackgroundDeveloping a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells’ proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection.MethodsUsing 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets.ResultsAn exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature’s negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell–mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature’s negative predictive value was 90.6% and its positive predictive value was 77.8%.ConclusionsOur findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.     

凝血酶对人重组内皮细胞衍生IL—8融合蛋白转换作用

本文报道利用基因工程技术在大肠杆菌中表达出入内皮细胞衍生IL-8(EDhIL-8)与细菌蛋白lacZ 的融合蛋白lac-hIL-8和lac-T-hIL-8,后者含有一个人工合成凝血酶切点。EDhIL-8上含有一个凝血酶切点,凝血酶可以将lac-hIL-8及以前表达的MS2-hIL-8水解为有生物活性的天然IL-8,而对含有两个凝血酶切点的lac-T-hIL-8无水解作用。这些结果提示凝血酶的功能不仅依赖于所识别的氨基酸,而且依赖于这些氨基酸形成的构象。     

胶质细胞源性神经营养因子在小鼠生精恢复过程中的表达和意义

目的:分析并探讨胶质细胞源性神经营养因子(GDNF)在小鼠恢复生精过程中的表达变化,及其与精原干细胞增殖与分化的关系。方法:间隔24 d 2次腹腔注射白消安建立小鼠生精恢复过程的动物模型。根据第二次给药后的不同时间随机分为1、2、3、4、6、8、10周共7组(8只/组),8只正常小鼠作对照组,分别于相应时点取材,进行光镜和电镜的研究。采用半定量逆转录聚合酶链反应(RT-PCR)检测不同时间GDNF mRNA的表达变化;并采用原位杂交技术检测GDNFmRNA表达定位。结果:2次给药后第1-2周,GDNF mRNA的表达明显增强,在第2周达到高峰;在给药后第3-4周明显下降,并在第4周达到低谷;随后几周内表达又逐渐增强,于第10周恢复到正常水平。原位杂交显示,GDNF由sertoli细胞表达。结论:在小鼠生精恢复过程中,GDNF的高水平表达促进精原干细胞自我更新,对于维持生精上皮干细胞数量的稳定具有十分重要的意义。     

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?? Chemokine stromal cell-derived factor-1??SDF-1??has characteristics of cell migration and is expected to be used in the field of oral tissue repair and regeneration. When the damage occurs in the body's tissues and organs??impaired cells secret and express SDF-1 and recruit bone marrow-derived stem cells or progenitor cells to the injured site??so as to promote the repair of damaged tissue by providing the new blood vessels and cells. This paper summarizes the effect of SDF-1 in oral tissue repair and the direction of future researches of the SDF-1.