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Chinese scholars gain the world's first genetic enhancement of human vascular cells: resistance to decay

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The gene editing technology, the "Magic Scissor" has been favored by scientists in various fields since its inception. Using this "magic cut" on the germ cells to create "superhuman" passed down from generation to generation, is not yet allowed by ethics. But on other cells licensed by ethics, scientists are trying to use this weapon to break the ceiling currently facing human disease treatment.

Chinese scholars gain the world's first genetic enhancement of human vascular cells: resistance to decay -Chinese-scholars-gain-the-world39s-first-genetic-enhancement-of-human-vascular-cells-resistance-to-decay

In the early morning of January 18th, Beijing time, Cell Stem Cell, the world's top journal in the field of stem cells, published 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 Institute of Zoology of the Chinese Academy of Sciences. The joint research results of the static research group: The world's first genetically enhanced human vascular cells were produced by targeted editing of a single longevity gene.

What is genetically enhanced human vascular cells? Liu Guanghui said in an interview with 澎湃News (www.thepaper.cn) that “the cells are 'optimized' in genetic and genetic traits. In the image, this 'enhancement’ is a mark on the genome, To play a lasting role. For example, some elderly people with longevity are not prone to illness, are not prone to cancer, and genetic factors are at work."

It is worth noting that this is the result of Liu Guanghui and others for six years, and the starting material is human embryonic stem cells. Stem cell-based human disease research, genetic and epigenetic information decoding of human aging, and novel genome editing techniques are all areas of Liu Guanghui's expertise. "With regard to the clinical application of stem cells or gene therapy, one of the two biggest concerns is that : Is it effective enough? Is it safe enough? If these two points are solved, it can be further clinically." Liu Guanghui said.

Starting from human embryonic stem cells, genetically enhanced stem cells are obtained through gene editing techniques, and further differentiated to obtain genetically enhanced vascular cells – a seemingly uncomplicated path that currently seems to be a breakthrough in stem cell treatment.

The paper mentions that these vascular cells can not only promote vascular repair and regeneration more effectively than wild-type vascular cells, but also effectively resist the tumorigenic transformation of cells. The successful acquisition of genetically enhanced human vascular cells provides an important solution for safe and effective clinical cell therapy.

Chinese scholars gain the world's first genetic enhancement of human vascular cells: resistance to decay -1547796316_234_Chinese-scholars-gain-the-world39s-first-genetic-enhancement-of-human-vascular-cells-resistance-to-decay

Human vascular cells with enhanced FOXO3 function are produced by gene editing for the treatment of ischemic vasculopathy.

Why do we have genetic enhancement for stem cells?

The research team used "magic scissors" on embryonic stem cells, which begins with the current state of stem cell therapy.

So-called stem cells are a kind of self-replicating cells that can differentiate into multiple functional cells under certain conditions. Among them, embryonic stem cells have the greatest potential for differentiation, and "theoretically can produce different types of cell therapy products", which means that all kinds of damaged tissues or organs will have hope for regeneration.

However, there are currently two issues that need to be addressed in this area: effectiveness and security.

Targets for stem cell therapy are currently generally focused on the elderly or patients with refractory diseases. In the specific treatment, Liu Guanghui mentioned that "the site where the disease is damaged will attack the cells implanted from the foreign source. This attack does not refer to immune rejection, but to the poor microenvironment derived from aging and disease. Inflammatory factors, Oxygen free radicals, toxic metabolites, etc. all attack foreign cell transplants." This will directly lead to the "death" of transplanted cells that have not yet functioned.

It can be seen that the ideal stem cell or cell therapy should be that after the cell is transplanted into the body, it does not need to be frequently injected, and it can resist the local micro-environment and can function for a long time until the damaged part is repaired. Good, effective regeneration. “This is an ideal state and it is still difficult to achieve.”

In addition to seeing no effect, another big concern is the formation of tumors. "This is the key to the widespread use of cell therapy technology. Many people still have a cautious attitude toward the possible cancer risk in stem cell therapy, even if there is great hope for this treatment." Liu Guanghui pointed out.

Then, if we break through the conventional thinking and allow transplanted cells to adapt to the undesirable micro-environment under abnormal physiological conditions, can we fundamentally solve the two "blockers" of efficacy and safety?

The first "one stone two birds" strategy

The research team anchored the target to a transcription factor called "FOXO3."

A transcription factor, as its name suggests, is a protein that assists in the transcription of genetic material DNA into RNA. The FOXO3 transcription factor binds to the promoter region of the gene and upregulates some gene transcription.

The key point is that FOXO3 is considered to be an important human longevity protein, which is almost universal in people all over the world. Previous studies have shown that FOXO3 is closely related to delaying cell senescence, resisting external stress and enhancing cardiovascular homeostasis. Furthermore, activation of FOXO3 can counteract malignant transformation of cells by inducing tumor suppressor gene expression.

In human embryonic stem cells, the team used the third-generation adenoviral vector HDAdV-mediated gene editing technology to subtly replace two single nucleotides in exon 3 of the FOXO3-encoding gene. Changing two single nucleotides is like a "four or two" for the vast genomic ocean.

Once the two nucleotides are altered, the corresponding encoded protein FOXO3 will have two amino acid variations at the amino acid level. Normally, these two amino acids are phosphorylated by the protein kinase Akt in the cell, and then FOXO3 is transported from the nucleus to the cytosol and then degraded. The amino acid mutation can not be effectively phosphorylated by Akt, which means that the encoded protein FOXO3 can "stay" in the nucleus for a longer period of time, so as to better play its role.

The research team then directed the above-mentioned FOXO3 genetically enhanced human embryonic stem cells into vascular endothelial cells (endometrial), vascular smooth muscle cells (vascular lining) and interstitial cells (vascular envelope). Experiments have shown that these three vascular cells show stronger self-renewal, resistance to oxidative damage and delayed cell senescence than wild-type cells. In terms of mechanism, the paper mentions that endogenously activated FOXO3 mediates the resistance to vascular cell senescence by antagonizing CSRP1 gene expression.

Further, the research team also conducted experiments on mice on vascular cells differentiated from the above-described genetically enhanced human embryonic stem cells. In the experiment, the large blood vessels in the leg of the mouse were ligated and an ischemic injury occurred. As a result, the researchers injected human enhanced vascular cells into the legs of the mice to help the injured legs of the mice re-regenerate the vascular system.

The results showed that enhanced vascular cell transplantation can effectively promote the regeneration of damaged blood vessels and rapidly restore the blood flow in the ischemic area, which proves that these cells have significantly better vascular repair ability than wild-type cells.

The effect is good, can the problem of tumorigenicity be solved?

To validate the safety of genetically enhanced stem cells as a graft material, the researchers designed an extreme environment for them: introducing multiple carcinogenic factors into wild-type and genetically enhanced stem cells. It was found that genetically enhanced stem cells were also effective against oncogene-induced malignant transformation of cells. "Not only did not form a tumor, but also acquired the ability to resist tumors." Liu Guanghui said.

Chinese scholars gain the world's first genetic enhancement of human vascular cells: resistance to decay -1547796316_767_Chinese-scholars-gain-the-world39s-first-genetic-enhancement-of-human-vascular-cells-resistance-to-decay

FOXO3-enhanced human vascular cells are highly resistant to cell carcinoma.

The research team pointed out that by rewriting two bases in the human genome, the research team successfully established high-quality human vascular cells that can simultaneously resist cell aging and cancer. Liu Guanghui believes that this actually achieves the effect of “one stone and two birds”: both the enhancement of therapeutic ability and the ability to resist tumors.

In the field of cell therapy and in situ regeneration, the research team's work is a world-first strategy.

Chinese scholars gain the world's first genetic enhancement of human vascular cells: resistance to decay -1547796317_959_Chinese-scholars-gain-the-world39s-first-genetic-enhancement-of-human-vascular-cells-resistance-to-decay

Enhanced function of FOXO3 can delay vascular aging, enhance stress resistance and prevent cell cancer.

It is worth noting that the research team has published relevant papers on this kind of treatment strategy for genetic enhancement. In 2017, the same research team published a paper to obtain the first genetically enhanced human stem cells in the world. “The idea is the same, but this time it is edited for the human longevity gene and is focused on validation in the vascular degenerative disease system.”

Is this pioneering strategy proliferating and showing its talents in other disease areas?

For this, Liu Guanghui emphasized that in addition to the above-mentioned effect of "one stone and two birds", the team's technical route is to use human embryonic stem cells as a starting material.

"Human embryonic stem cells can be expanded in large quantities in vitro, and can be induced to differentiate into any cell type with therapeutic potential in the laboratory. In the future, genetic enhancement strategies may help standardize human quality cell therapy products. Liu Guanghui said.


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