Targeted editing of longevity genes to make old and weak blood vessels "Q-slip smooth" February 20, 2019 Source: Science and Technology Daily Author: Zhang Jia Xing It is said that the length of the blood vessels in the human body can reach more than 100,000 kilometers, and the blood runs between them every day. Some are "high-speed roads", some are "national roads", and some are "country roads". The “new road†tends to be smooth and smooth, and the “old road†tends to be pitted and smashed. Is it possible to repair the “old road†through biotechnology? Recently, "Cell Stem Cell" published online the joint research results of the Liu Guanghui Research Group of the Institute of Biophysics of the Chinese Academy of Sciences, the Tang Fuyue Research Group of Peking University and the Qujing Research Group of the Institute of Zoology of the Chinese Academy of Sciences - by targeting individual long-lived genes. Obtained the first genetically enhanced human vascular cells. "We performed gene editing in human embryonic stem cells, directed differentiation of the edited stem cells, and obtained human vascular endothelial cells (endometrial), vascular smooth muscle cells (vascular lining) and interstitial cells in the laboratory ( "Vascular outer membrane"." Liu Guanghui, a researcher at the Institute of Biophysics, Chinese Academy of Sciences, one of the authors of the paper, said that genetically enhanced human vascular stem cells are expected to become old and weak vascular "patches" to help repair aging and damaged blood vessels, which may be applied in the future. In the treatment of diseases such as myocardial infarction and ischemic stroke. Adenoviral vector-mediated selection of "non-mainstream" editor When it comes to gene editing, the CRISPR/Cas9 technology is famous. It is also called “three great tools†for ZFN and TALEN technology. However, the gene editing technology selected this time is not one of them, but an adenoviral vector (HDAdV)-mediated gene editing technology called helper virus dependence. This name that cannot be read at a time needs to be split to understand. The adenoviral vector is the effective core of this "gene editor", which can be "swallowed" by the cells, and does not stop at the cytoplasm, but can enter the nucleus, because the genes should be edited, rewritten, erased, etc. Such operations must be carried out in the "base camp" nucleus of the gene. However, the adenoviral vector will remain extrachromosomal and will not integrate into the host cell genome, so it will not cause damage to the human genome. "We use the third-generation adenoviral vector, which lacks the genomic sequence of the adenovirus, thus greatly reducing the toxicity of the viral vector." Liu Guanghui said, it can be understood that, after technical transformation, only the adenovirus "loading and unloading" is retained. The function, and its virus features have been completely abandoned. When the DNA homologous recombination sequence carried by the "HDAdV Adenovirus" truck enters the nucleus, the search and replacement of the genomic target sequence is automatically completed. "HDAdV technology completely utilizes the principle of homologous recombination of large fragment DNA for gene editing, and generally does not cause off-target effects like CRISPR/Cas9." Liu Guanghui introduced that it can carry ultra-long DNA fragments of up to 25-37 kb into human nucleus. , replace the intrinsic fragments of the genome, and thus achieve efficient and accurate gene editing. The more sophisticated the technology is, the research on the application of HDAdV technology by Liu Guanghui's research group has accumulated for many years. As early as 2011, Liu Guanghui and others used HDAdV gene editing technology to achieve high-efficiency and accurate correction of disease-causing gene mutations in human disease stem cells for the first time. Research team graduate Yan Pengze said in an interview that the CRISPR/Cas9 technology has just been introduced and has not been used in human cells. The laboratory has been skilled in using HDAdV technology to correct or knock in several human pathogenic gene mutations. At the same time, the safety of HDAdV gene editing technology has been proved. The related articles are published in "Nature", "Science", "Cell" and "Cell Stem Cell" magazines. In 2017, the research team produced the first genetically enhanced human mesenchymal stem cells in the world through HDAdV technology. Editing the FOXO3 gene, it is the longevity world. If a worker wants to do something good, he must first sharpen his tools. With the skill and skill of pickpockets, which genes should be edited to make the vascular cells "young"? "FOXO3 is the most conservative and recognized gene associated with longevity." Liu Guanghui said that the FOXO family is a class of transcription factors. In the 1990s, scientists discovered that FOXO family homologous proteins may be involved in the regulation of animal life. As the research progressed, scientists found that the FOXO3 gene is indeed related to human longevity. Further research is fine to a single nucleotide. The basic idea is to compare the FOXO3 gene in the 100-year-old elderly population with the average life expectancy of 78.5 years old, find the nucleotide variation in this region, and gradually narrow down the range of sites directly related to longevity. Further research shows that people in many countries can find longevity-related nucleotide variations in the FOXO3 gene. The research team decided to edit the FOXO3 gene, and because it can play the role of "one stone and two birds." The application of stem cells to the human body is actually very difficult. It is like balancing the "seesaw". The state of stem cells must be just right. If it is too "crazy", it may become a tumor. If it is too "weak", it may be destroyed by the body. "The study found that FOXO3 has a function of maintaining vascular homeostasis." Liu Guanghui said that it is a transcription factor that activates multiple downstream cell-protected signaling pathways. Activation of FOXO3 can also prevent tumor formation by inducing tumor suppressor gene expression. Therefore, the choice of FOXO3 can simultaneously improve the efficiency and safety of cell therapy. To prove this, the team also introduced a variety of carcinogenic factors into genetically enhanced vascular cells and found that it is also effective against oncogene-induced malignant transformation of cells, which greatly reduces the safety risks of using these cells for treatment. Stem cells have taken a solid step toward clinical application. Is "throttle" is not "open source" regulation of cell operation "management" The FOXO3 protein encoded by the FOXO3 gene is essentially a transcription factor. Its working place is in the nucleus, and it is combined with the specific sequence specificity of the gene to ensure that the gene expression is "ordered" and "regular". To put it bluntly, they are the "management" of the life of a cell. There is also a “bomb†system for “management†within the cell. Under certain conditions, such as the cell feels "satisfied", the FOXO3 protein is phosphorylated by the PI3K/AKT pathway, and the protein is labeled with a phosphorylation. These FOXO3 proteins are then "captured". The activity is suppressed, and finally "down step" is taken out of the nucleus. "Understanding this regulatory mechanism, we chose 'throttle' instead of 'open source'." Liu Guanghui said that in order to minimize the genomic changes, the research team did not enhance FOXO3 gene expression, but ensured by 2 base substitution. FOXO3 protein is not "bombed" and "re-elected". "We replaced two single nucleotides in exon 3 of the FOXO3 gene in human embryonic stem cells using HDAdV-mediated gene editing technology, rendering the FOXO3 protein transcription factor ineffectively phosphorylated by AKT, thereby inhibiting FOXO3 Phosphorylation and degradation of proteins promotes the accumulation of FOXO3 in the nucleus and activates the expression of downstream 'beneficial' target genes. Maximizes the integrity of the human genome by precisely editing two nucleotides in the human genome. Liu Guanghui said. After genetically edited stem cells were differentiated into different genetically enhanced human vascular cells, relevant animal experiments were performed. Experiments have shown that after the artificial aortic vessels in the leg of the mouse are artificially ligated, the road that transports blood to the legs is sealed. When the genetically enhanced vascular cells were injected into the leg, the former had stronger self-renewal, resistance to oxidative damage, and delayed cell senescence than the control group injected with un-enhanced, unedited vascular cells. It can effectively promote the regeneration of damaged blood vessels and quickly restore blood flow in the ischemic area. Wireless Camera Kits With 4 Camera
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