Recent approval of exagamglogene autotemcel(exa-cel)on November 16,2023,in the United Kingdom,developed by Vertex Pharmaceuticals and CRISPR Therapeutics,represents the first cell-based therapy for treatment of sickle...Recent approval of exagamglogene autotemcel(exa-cel)on November 16,2023,in the United Kingdom,developed by Vertex Pharmaceuticals and CRISPR Therapeutics,represents the first cell-based therapy for treatment of sickle cell disease(SCD)with recurrent vaso-occlusive crises(VOCs)or transfusion-dependentβ-thalassemia(TDT)in patients aged 12 and above.Following suit,the US Food and Drug Administration authorized exa-cel for the same indications on December 8,2023.Exa-cel represents the first commercially approved CRISPR-based gene therapy,offering hope to approximately 25,000 eligible patients in the US and Europe.The significance of exa-cel extends beyond revolutionizing therapeutic intervention in genetic medicine;it also raises profound ethical considerations and societal implications related to genome manipulation.展开更多
Leucine-rich repeat containing G protein-coupled receptor 5(Lgr5), a marker of intestinal stem cells(ISCs), is considered to play key roles in tissue homoeostasis and regeneration after acute radiation injury. However...Leucine-rich repeat containing G protein-coupled receptor 5(Lgr5), a marker of intestinal stem cells(ISCs), is considered to play key roles in tissue homoeostasis and regeneration after acute radiation injury. However, the activation of Lgr5 by integrated signaling pathways upon radiation remains poorly understood. Here, we show that irradiation of mice with whole-body depletion or conditional ablation of REGγ in Lgr5^(+) stem cell impairs proliferation of intestinal crypts, delaying regeneration of intestine epithelial cells. Mechanistically, REGγ enhances transcriptional activation of Lgr5 via the potentiation of both Wnt and Hippo signal pathways. TEAD4 alone or cooperates with TCF4, a transcription factor mediating Wnt signaling, to enhance the expression of Lgr5. Silencing TEAD4 drastically attenuated β-catenin/TCF4 dependent expression of Lgr5. Together, our study reveals how REGγ controls Lgr5 expression and expansion of Lgr5+stem cells in the regeneration of intestinal epithelial cells.Thus, REGγ proteasome appears to be a potential therapeutic target for radiation-induced gastrointestinal disorders.展开更多
基金CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-041 to S.R.)Science,Technology&Innovation Project of Xiongan New Area(2022XAGG0142 to S.R.)We thank Dr.Ke Chen for coordinating the submission of the manuscript.
文摘Recent approval of exagamglogene autotemcel(exa-cel)on November 16,2023,in the United Kingdom,developed by Vertex Pharmaceuticals and CRISPR Therapeutics,represents the first cell-based therapy for treatment of sickle cell disease(SCD)with recurrent vaso-occlusive crises(VOCs)or transfusion-dependentβ-thalassemia(TDT)in patients aged 12 and above.Following suit,the US Food and Drug Administration authorized exa-cel for the same indications on December 8,2023.Exa-cel represents the first commercially approved CRISPR-based gene therapy,offering hope to approximately 25,000 eligible patients in the US and Europe.The significance of exa-cel extends beyond revolutionizing therapeutic intervention in genetic medicine;it also raises profound ethical considerations and societal implications related to genome manipulation.
基金supported by the National Natural Science Foundation of China (82073483, 31730017, 82022051)the Science and Technology Commission of Shanghai Municipality (19JC1411900, 20s11901500)Changning Maternity and Infant Health Hospital PI team building project (311-20031)。
文摘Leucine-rich repeat containing G protein-coupled receptor 5(Lgr5), a marker of intestinal stem cells(ISCs), is considered to play key roles in tissue homoeostasis and regeneration after acute radiation injury. However, the activation of Lgr5 by integrated signaling pathways upon radiation remains poorly understood. Here, we show that irradiation of mice with whole-body depletion or conditional ablation of REGγ in Lgr5^(+) stem cell impairs proliferation of intestinal crypts, delaying regeneration of intestine epithelial cells. Mechanistically, REGγ enhances transcriptional activation of Lgr5 via the potentiation of both Wnt and Hippo signal pathways. TEAD4 alone or cooperates with TCF4, a transcription factor mediating Wnt signaling, to enhance the expression of Lgr5. Silencing TEAD4 drastically attenuated β-catenin/TCF4 dependent expression of Lgr5. Together, our study reveals how REGγ controls Lgr5 expression and expansion of Lgr5+stem cells in the regeneration of intestinal epithelial cells.Thus, REGγ proteasome appears to be a potential therapeutic target for radiation-induced gastrointestinal disorders.