Chinese scientists set up a faster and more efficient reprogramming system for human cytochemistry.

　　Peking University Deng Hongkui’s research group recently published a research paper entitled "Efficient and Rapid Preparation of Human Pluripotent Stem Cells by Chemical Reprogramming" in the international academic journal Cell Stem Cells. In this study, a new chemical reprogramming system was established to induce human adult cells into pluripotent stem cells more quickly and efficiently.
　　According to the team members, pluripotent stem cells have the ability of infinite self-renewal and differentiation into all functional cell types of organisms. These magical characteristics make them widely used in cell therapy, drug screening and disease models, and they are the most critical "seed cells" in the field of regenerative medicine. How to induce pluripotent stem cells in vitro has always been a key scientific problem in the field of life science. In 2013, Deng Hongkui’s research group published an original achievement in the journal Science, that is, it can reverse the fate of cells without relying on endogenous substances such as oocytes and transcription factors, and reprogram mouse somatic cells into pluripotent stem cells (CiPS cells), opening up a new path of somatic cell reprogramming. In 2022, Deng Hongkui’s research group made a new breakthrough and successfully realized the induction of human adult cells into pluripotent stem cells (human CiPS cells) by using small chemical molecules.
　　The essence of life is a chemical process, and it is theoretically the most effective way to regulate the fate of cells through small chemical molecules. There are essential differences between chemical reprogramming and traditional reprogramming technology: traditional transgenic reprogramming technology, such as induced pluripotent stem cell technology (iPS technology), drives the cell fate to change directly through the over-expression of endogenous transcription factors, and its induction process is difficult to control; Chemical reprogramming is to use exogenous chemical small molecules to simulate external signal stimulation and drive the cell fate to change in stages. Therefore, this method has strong controllability, and it is expected to achieve precise regulation of cell fate, reverse cell identity and functional state, and make reverse development possible.
　　In this latest research achievement, Deng Hongkui has established a faster, more efficient and more stable reprogramming method of human cytochemistry. The researchers discovered a new combination of small chemical molecules, which greatly accelerated the reprogramming process. The induction period was shortened from 50 days to less than 30 days, and the induction could be completed in 16 days at the shortest. At the same time, the induction efficiency is greatly improved, up to 31%. The new system was tested on somatic cells from 17 individuals with different genetic backgrounds and different ages, and all of them could be induced efficiently, which accelerated the wide application of human CiPS cells in cell therapy, drug screening and disease models.
　　According to the previous report of the research group, the original system went through the stages of epithelioid cells, plastic intermediate cells and XEN-like cells in the process of inducing human CiPS cells, and finally established pluripotent stem cells. However, this study found that the molecular mechanism of the new system is faster and more efficient: the proliferation ability and oxidative phosphorylation metabolic activity of plastic intermediate cells are significantly enhanced, and they no longer go through XEN-like stage, and the pluripotent genes are activated faster and the molecular path is more direct. It is particularly important that traditional iPS reprogramming relies on the process of glycolysis and metabolism, while the most critical stage of chemical reprogramming-the production of plastic intermediate state depends on oxidative phosphorylation, not glycolysis and metabolism. This discovery reveals the importance of specific energy metabolism pathways to the fate transformation process of different cells, and provides a new perspective for understanding the regulation mechanism of cell fate from the perspective of energy metabolism.
　　In addition, the new induction scheme established in this study is not only fast, efficient and stable, but more importantly, it has clear components, and does not depend on serum or feeder cells. These properties better meet the needs of clinical application, laying a foundation for establishing human CiPS cell lines that meet the clinical application standards and making it a key step towards clinical application. Compared with transgenic over-expressed transcription factors, chemical small molecules have the advantages of not integrating genome, reversible action and simple operation, so CiPS technology is safer, simpler and easier to standardize, and has broad clinical application prospects. At present, Deng Hongkui’s research group has efficiently prepared islet cells from human CiPS cells, and verified its safety and effectiveness in treating diabetes in large animal models, highlighting the clinical application value of human CiPS cells as "seed cells" in treating major diseases.