Tuft cells act as regenerative stem cells in the human intestine 公告 2024-10-02 14:53:03 Written By Kym Kilbourne Title: Tuft Cells Act as Regenerative Stem Cells in the Human Intestine Research Background and Significance In mice, intestinal tuft cells have been characterized as a long-lived, post-mitotic cell type. They are divided into two distinct subpopulations: tuft-1 and tuft-2. Most of the knowledge regarding the ontology and function of tuft cells originates from mouse studies due to the lack of human ex vivo tuft cell models. Mouse tuft cells differ between tuft-1 cells, which express neuronal genes, and tuft-2 cells, primarily involved in protective immune responses. Although LGR5+ cells are the "main force" stem cells of the intestinal epithelium, they are highly sensitive to damage, and there are multiple compensatory mechanisms in mice to compensate for stem cell loss. The lack of models to study human tuft cell biology has hindered a detailed characterization and understanding of these cells' functions and characteristics, and human intestinal regenerative stem cells have not yet been identified. The significance of this study lies in revealing the status of human intestinal tuft cells and their role as a stem cell pool in damage responses. Research Introduction The research team identified four distinct human tuft cell states by analyzing primary human intestinal resection materials and intestinal organoids, two of which overlap with the corresponding subpopulations in mice. The study shows that the development of tuft cells depends on the presence of Wnt ligands, and under the influence of interleukin-4 (IL-4) and IL-13, the number of tuft cells increases rapidly, achieved through the proliferation of existing tuft cells rather than the de novo generation of stem cells. The study also found that mature proliferating tuft cells can form organoids containing all types of intestinal epithelial cells in vivo, and unlike stem cells, human tuft cells can tolerate radiation damage and maintain the ability to generate all other epithelial cell types. Research Highlights Identified four human tuft cell states, and found that two of them overlap with mouse tuft cell subpopulations. Discovered that tuft cells can rapidly proliferate under the influence of IL-4 and IL-13, and this proliferation is independent of stem cells. Confirmed that a single mature proliferating tuft cell can form organoids containing all types of intestinal epithelial cells, indicating that tuft cells possess stem cell-like attributes. Found that tuft cells can recover after radiation damage, while organoids lacking tuft cells cannot recover from radiation-induced damage, indicating that tuft cells are a reserve stem cell pool for human intestinal damage induction. Research Results Successfully generated a human intestinal organoid clonal line by CRISPR-assisted non-homologous end joining at the AVIL locus with green fluorescent protein (mClover), and observed the importance of Wnt signaling in tuft cell differentiation. IL-4 and IL-13 can induce significant proliferation of tuft cells, which is achieved through the proliferation of existing tuft cells, not the de novo generation of stem cells. Through single-cell RNA sequencing analysis, the research team found that under homeostatic conditions, the main tuft cell subpopulations are tuft-1 and tuft-2, and under IL-4 signaling, periodic tuft-3 cells are induced and tuft-4 is significantly expanded. A single tuft cell can form organoids containing all types of intestinal epithelial cells, demonstrating the stem cell-like regenerative potential of tuft cells. Research Significance This study provides a detailed classification of human intestinal tuft cells and reveals their stem cell characteristics in damage responses, offering a new perspective for intestinal regenerative medicine. The results suggest that targeting cytokines such as IL-4 and IL-13 can enhance the regenerative response of tuft cells, which may be significant for the treatment of intestinal damage and diseases. Given the widespread presence of tuft cells in other endoderm-derived tissues, these findings may also be enlightening for studying the potential regenerative roles of tuft cells in other tissues, such as the biliary tract, urinary tract, and airways. Paper Link https://pmc.ncbi.nlm.nih.gov/articles/PMC11499303/ Kym Kilbourne
Tuft cells act as regenerative stem cells in the human intestine 公告 2024-10-02 14:53:03 Written By Kym Kilbourne Title: Tuft Cells Act as Regenerative Stem Cells in the Human Intestine Research Background and Significance In mice, intestinal tuft cells have been characterized as a long-lived, post-mitotic cell type. They are divided into two distinct subpopulations: tuft-1 and tuft-2. Most of the knowledge regarding the ontology and function of tuft cells originates from mouse studies due to the lack of human ex vivo tuft cell models. Mouse tuft cells differ between tuft-1 cells, which express neuronal genes, and tuft-2 cells, primarily involved in protective immune responses. Although LGR5+ cells are the "main force" stem cells of the intestinal epithelium, they are highly sensitive to damage, and there are multiple compensatory mechanisms in mice to compensate for stem cell loss. The lack of models to study human tuft cell biology has hindered a detailed characterization and understanding of these cells' functions and characteristics, and human intestinal regenerative stem cells have not yet been identified. The significance of this study lies in revealing the status of human intestinal tuft cells and their role as a stem cell pool in damage responses. Research Introduction The research team identified four distinct human tuft cell states by analyzing primary human intestinal resection materials and intestinal organoids, two of which overlap with the corresponding subpopulations in mice. The study shows that the development of tuft cells depends on the presence of Wnt ligands, and under the influence of interleukin-4 (IL-4) and IL-13, the number of tuft cells increases rapidly, achieved through the proliferation of existing tuft cells rather than the de novo generation of stem cells. The study also found that mature proliferating tuft cells can form organoids containing all types of intestinal epithelial cells in vivo, and unlike stem cells, human tuft cells can tolerate radiation damage and maintain the ability to generate all other epithelial cell types. Research Highlights Identified four human tuft cell states, and found that two of them overlap with mouse tuft cell subpopulations. Discovered that tuft cells can rapidly proliferate under the influence of IL-4 and IL-13, and this proliferation is independent of stem cells. Confirmed that a single mature proliferating tuft cell can form organoids containing all types of intestinal epithelial cells, indicating that tuft cells possess stem cell-like attributes. Found that tuft cells can recover after radiation damage, while organoids lacking tuft cells cannot recover from radiation-induced damage, indicating that tuft cells are a reserve stem cell pool for human intestinal damage induction. Research Results Successfully generated a human intestinal organoid clonal line by CRISPR-assisted non-homologous end joining at the AVIL locus with green fluorescent protein (mClover), and observed the importance of Wnt signaling in tuft cell differentiation. IL-4 and IL-13 can induce significant proliferation of tuft cells, which is achieved through the proliferation of existing tuft cells, not the de novo generation of stem cells. Through single-cell RNA sequencing analysis, the research team found that under homeostatic conditions, the main tuft cell subpopulations are tuft-1 and tuft-2, and under IL-4 signaling, periodic tuft-3 cells are induced and tuft-4 is significantly expanded. A single tuft cell can form organoids containing all types of intestinal epithelial cells, demonstrating the stem cell-like regenerative potential of tuft cells. Research Significance This study provides a detailed classification of human intestinal tuft cells and reveals their stem cell characteristics in damage responses, offering a new perspective for intestinal regenerative medicine. The results suggest that targeting cytokines such as IL-4 and IL-13 can enhance the regenerative response of tuft cells, which may be significant for the treatment of intestinal damage and diseases. Given the widespread presence of tuft cells in other endoderm-derived tissues, these findings may also be enlightening for studying the potential regenerative roles of tuft cells in other tissues, such as the biliary tract, urinary tract, and airways. Paper Link https://pmc.ncbi.nlm.nih.gov/articles/PMC11499303/ Kym Kilbourne
