Targeted editor FOXO3 produces the world's first genetically enhanced human vascular cells.

Stem cell technology has a broad application prospect in regenerative medicine. After transplanting many types of cells from in vitro induced differentiation of stem cells into the lesions site, the
can achieve the goal of promoting the regeneration of diseased tissues and restoring the steady state and function of tissue organs.
However, stem cell therapy is limited in its effectiveness and safety, hindering its popularity.
the Liu Guanghui Research Group of the Institute of Biophysics of the Chinese Academy of Sciences, the Tang Fuli Research Group of Peking University and the Qu Jing Research Group of the Institute of Zoology of the Chinese Academy of Sciences jointly conducted a joint study to produce the world's first genetically enhanced human vascular cells by targeting a single longevity gene.
these vascular cells can not only promote vascular repair and regeneration more efficiently than wild vascular cells, but also effectively resist tumor-causing transformation of cells. the successful acquisition of
genetic enhancement of human vascular cells provides an important solution for safe and effective clinical cell therapy.
the study was published on 18 January in Cell Stem Cell under the theme foxO3-engineered human ESC-derived cells sex man marquee and resell.
FOXO3 is an important human longevity gene, which is closely related to delaying cell aging, resisting external stress and enhancing cardiovascular stability.
, the activation of FOXO3 can resist the malignant transformation of cells by inducing the expression of cancer-suppressing genes.
researchers spent six years exploring, and finally used the third-generation adenovirus vector HDAdV-mediated gene editing technology to subtly replace two single nucleotides in the FOXO3 gene in human embryonic stem cells, thus suppressing the phosphorylation and degradation of foxO3 proteins in cells, and promoting the aggregation of FOXO3 in the nucleus to activate the expression of downstream target genes.
when FOXO3 genetically activated human embryonic stem cells were directed into vascular endothelial cells (vascular endothelial), vascular smooth muscle cells (vascular midmymes) and interstitial cells (vascular outer membranes), all three blood vessel cells showed stronger self-renewal, resistance to oxidative damage and delayed cell aging than wild cells.
mechanism, endogenously activated FOXO3 acts as an tagonic CSRP1 gene expression mediated resistance to vascular cell aging.
more importantly, the targeting of genetically enhanced human vascular cells to ischemia in animal models can effectively promote the regeneration of damaged blood vessels and quickly restore blood flow at ischemia sites, proving that these cells have significantly better vascular repair capabilities than wild-type cells.
to test the safety of genetically enhanced stem cells as a transplanted material, researchers introduced a variety of carcinogenic factors into wild and genetically enhanced stem cells, and found that genetically enhanced stem cells can also effectively resist cancer-induced cell malignant transformation.
, by rewriting the two bases in the human genome, the team has succeeded in building high-quality human vascular cells that can simultaneously resist cell aging and cancer.
the study used gene editing technology for the first time to enhance the function of human vascular cells, revealed the longevity protein FOXO3 to maintain the stable state of human blood vessels, and conceptually proved the feasibility of using gene editing strategies to obtain high-quality and safe human vascular cell transplantation. In addition,
, the study makes it possible to scale and standardize the preparation of high-quality and safe human cell therapies, providing potential options for future regenerative medicine and has far-reaching implications for the development of safer and more effective clinical cell therapy strategies.
Liu Guanghui's team has long been committed to aging, stem cell and gene editing research, and has achieved a series of pioneering research results.
include: gene editing mediated by adenovirus vectors (HDAdV) that are assisted by virus dependence for the first time to achieve efficient correcti of disease-causing gene mutations in human stem cells (Cell Stem Cell 2011); More than 10 disease-causing gene mutations have been repaired or edited, and a series of disease research and drug screening platforms (Cell 2016, Science 2015, Nature 2012, Nature 2011, Nat Commun 2014, Cell Stem Cell 2011, Cell Res 2016; Cell Cell 2016, Aging Cell 2017) TTALE (Cell Res 2017), a 3D genome dynamic imaging tool based on the classic gene editing tool TALEN, and the world's first longevity gene knockout monkey model (Nature 2018) using CRISPR/Cas9.
this acquisition of genetically enhanced human vascular cells is another breakthrough in the field of regenerative medicine after Liu Guanghui's team created the world's first genetically enhanced human stem cell (Cell Res 2017) to combat cell aging and cancer in 2007.
these studies show that the genetic code of the human genome can be creatively rewritten and is expected to be safely and effectively applied to disease treatment.
the research was carried out by the Institute of Biophysics of the Chinese Academy of Sciences, the Institute of Zoology of the Chinese Academy of Sciences, the Institute of Stem Cell and Regeneration Innovation of the Chinese Academy of Sciences, Peking University, Xuanwu Hospital of Capital Medical University and other institutions.
Liu Guanghui, Tang Fuhui and Qu Jing are co-authors. Yan Pengze, a master's student at the
Institute of Biophysics, and Li Qingqing, a doctoral student at Peking University, were the first authors.
the project has been supported by the Ministry of Science and Technology, the National Natural Science Foundation of China and the Chinese Academy of Sciences.
Source: Institute of Biophysics.