z-bio 2025-07-30 3674

　　Professor Deng Hongkui's team of Peking University continued its leading position in the field of cell fate regulation in 2025. Since the beginning of the year, it has published 10 high-level research results, with a total impact factor of 130.5, covering many cutting-edge fields such as embryonic development, tumor treatment, and liver regeneration.

　　As the founder of chemical reprogramming technology, Deng Hongkui's team continued to expand the underlying technical boundaries of human pluripotent stem cell preparation through systematic innovation, providing key support for the clinical transformation of regenerative medicine. We have selected some articles with a score of more than 10 to share. For more excellent articles, please add them!

　　01

　　Cell Research

　　On July 4, 2025, Professor Deng Hongkui from Peking University, Qu Molong and Gu Jin, published a research paper entitled "A patient-derived organoid model captures fetal-like plasticity in colorectal cancer" at Cell Research (IF=25.9).

　　This study focused on the association between phenotypic plasticity and fetal-like transcriptional programs in colorectal cancer, established a patient-derived organoid system with clear chemical composition, and provided a reliable tool for in-depth study of the fetal-like characteristics of cancer cell plasticity in colorectal cancer and its role in tumor progression and treatment of drug resistance.

　　Phenotypic plasticity is a core driver of colorectal cancer (CRC) progression, metastasis, and therapeutic resistance, and fetal-like transcriptional procedures are considered key to promoting this plasticity, but existing research models limit the exploration of relevant mechanisms because they are unable to retain such characteristics for a long time.

　　To break through this limitation, the research team built a patient-derived organoid system with clear chemical composition: by replacing unstable recombinant proteins or animal-derived factors in traditional cultures (such as Noggin, R-spondin, etc.), the long-term expansion of colorectal cancer cells was achieved, while stably retaining fetal-like characteristics related to phenotypic plasticity.

　　Using this model, the team identified a carcinoembryonic state (OnFS): This state is highly enriched in advanced tumors and is closely related to the core plastic features of epithelial-mesenchymal transformation, enhanced metastasis ability and therapeutic drug resistance. At the mechanism level, studies have confirmed that the FGF2-AP-1 signaling pathway is a key regulatory axis for maintaining OnFS procedures and related phenotypic plasticity.

　　This model not only overcomes the shortcomings of fetal-like state prone to loss and signal in traditional organoid culture, but also provides a reliable platform for in-depth study of how fetal-like characteristics in colorectal cancer drive the plasticity of cancer cells and its role in tumor progression and drug resistance, laying the foundation for the development of therapeutic strategies for phenotypic plasticity.

　　02

　　GUT

　　On March 3, 2025, Deng Hongkui from Peking University and Pang Yuan from Tsinghua University published a research paper entitled "Bioprinting functional hepatocyte organizations derived from human chemically induced pluripotent stem cells to treat liver failure" at GUT (IF=23.1).

　　This study developed a three-dimensional bioprinting strategy based on hepatocyte organoids for the treatment of liver failure in response to the problem that traditional single-cell bioprinting liver tissue model has limited therapeutic effects due to insufficient cell function.

　　The research team used human chemically induced pluripotent stem cells (hCiPSCs) as the cell source, optimized oxygen supply through oxygen permeable microporous devices to generate high-vibration and high-functioning hepatic cell organoids (hCiPSC-HOs); then used spheroid-based bioprinting technology to construct liver tissue models (3DP-HOs) to maintain the long-term function of organoids.

　　Experimental results show that 3DP-HOs are more viable than single-cell models, have better gene expression, and can stably exert liver-specific functions. In animal experiments, 3DP-HOs peritoneal implantation significantly improved the survival rate of two liver failure models mice (CCl4-induced slow-acute liver failure and Fah⁻/⁻ liver failure), effectively alleviated liver damage, inflammation, and fibrosis, and promoted liver regeneration.

　　This study confirmed the significant efficacy of bioprinted hepatocyte organoid model in the treatment of liver failure, and provided a new solution for the clinical transformation of liver regenerative medicine.

　　03

　　Molecular therapy

　　On February 5, 2025, Deng Hongkui's team and Baiyun team jointly published a research paper titled "Potentiating CAR-T-cell function in the immunosuppressive tumor microenvironment by inverting the TGF-β signal" online on Molecular therapy (IF=12).

　　This study innovatively designed inverted cytokine receptor (ICR) to convert the inhibitory signal of TGF-β in the tumor microenvironment into the activation signal of IL-15, breaking through the limitations of the CAR-T cell function of solid tumor immunosuppressive microenvironment and providing a new strategy for the treatment of CAR-T cell in solid tumors.

　　In solid tumors, the TGF-β-dominated immunosuppressive microenvironment will inhibit the durability and function of CAR-T cells, while the existing TGF-β signaling blocking strategies are limited in efficacy. To this end, the research team designed a novel inverse cytokine receptor (ICR) modified CAR-T cell strategy: fusing the ectodomain of TGF-β receptor II with the intracellular domain of IL-15 receptor α (the construct is named TB15), and combining CARs targeting EGFR, so that T cells have the dual functions of "blocking TGF-β inhibitory signal" and "activate IL-15 stimulating signal".

　　In a mouse model of colorectal cancer with high TGF-β, this "signal inversion CAR-T cells (EGFR-CAR/TB15 T cells)" blocks the inhibition of CAR-T cells by TGF-β, and at the same time, IL-15 signaling promotes CAR-T cells proliferation and enhances their durability and cytotoxicity. Experiments have confirmed that this strategy significantly improves the survival and function of CAR-T cells in the solid tumor microenvironment and effectively inhibits tumor growth.

　　This study innovatively achieved the inversion of "inhibition signal → activation signal" through synthetic receptors, providing a new solution to overcome the key obstacles in CAR-T cell therapy in solid tumors and expanding the application of synthetic receptor signals in tumor immunotherapy.

　　04

　　SCIENCE CHINA Life Sciences

　　On January 13, 2025, Deng Hongkui, as co-corresponding author, published a research paper titled "Transient Chemical-Mediated Epigenetic Modulation Confers Unrestricted Lineage Potential on Human Primed Pluripotent Stem Cells" in the journal SCIENCE CHINA Life Sciences (IF=9.5).

　　Research is to address the problem of limited trophoblastic potential of human originating pluripotent stem cells (primed hPSCs), and a strategy for short-term treatment of cocktails through small molecule epigenetic regulators: while retaining the embryo differentiation potential, the treated cells obtain the trophoblastic potential, which can generate trophoblastic cells and downstream trophoblastic stem cells, and further differentiate into a fusion trophoblastic layer and an extravillous trophoblastic layer.

　　Transcriptome and epigenetic analyses confirmed that the transcriptional characteristics of the induced cells are highly similar to those of the trophoblast and trophoblasts in vivo, and that the H3K27me3 inhibition modifications are reduced in the trophoblast lineage gene loci. Mechanistically, inhibiting epigenetic regulatory factors such as HDAC2, EZH1/2, and KDM5s is the key to activate the potential of the trophoblast.

　　This study broke through the lineage limitations of the originating state hPSCs through transient epigenetic reset, not only revealing the mechanism by which epigenetic regulates the cellular pluripotent lineage potential, but also provides a reliable in vitro model for the study of placental development and related diseases.

　　05

　　Nature Chemical Biology

　　On January 3, 2025, Deng Hongkui's research team and Peking University Guan Jingyang's research team published a research paper entitled "A Rapid Chemical Reprogramming System to Generate Human Pluripotent Stem Cells" in the Nature sub-job Nature Chemical Biology (IF=13.7).

　　By comparing and analyzing somatic cells from different individual sources, the research team found it difficult to induce the enriched expression of histone modification-related enzymes KAT3A/B and KAT6A in cell lines, which is crucial to maintaining cell identity. By regulating these targets, the team established a new rapid chemical reprogramming system: the time for efficient induction of human CiPS cells from 30 days to within 16 days (the shortest is only 10 days), and efficient induction was achieved among 15 individual-derived somatic cells of different genetic backgrounds and ages, with a maximum efficiency of 38%. For donor cells with low reprogramming efficiency, the efficiency was increased by more than 20 times within 16 days, significantly enhancing the universality of the technology.

　　Mechanistically, inhibiting KAT3A/B and KAT6A can accelerate the closure of somatic genes, while putting the enhancer region that needs to be activated in the next stage in the epimodal state to be activated, promoting rapid transcription of these genes; it can also quickly break the somatic gene program, inhibit abnormal activation of genes, accelerate epigenetic modification changes, and achieve a more direct and universal transformation of cell fate.

　　In short, this study has improved the method of chemical reprogramming to prepare human pluripotent stem cells, provided a fast, efficient and stable underlying technology system, laying the foundation for the widespread application of regenerative medicine, clinical treatment and personalized medicine.