Lei Chen, Xia Qiu, Abigail Dupre, Oscar Pellon-Cardenas, Xiaojiao Fan, Xiaoting Xu, Prateeksha Rout, Katherine D Walton, Joseph Burclaff, Ruolan Zhang, Wenxin Fang, Rachel Ofer, Alexandra Logerfo, Kiranmayi Vemuri, Sheila Bandyopadhyay, Jianming Wang, Gaetan Barbet, Yan Wang, Nan Gao, Ansu O Perekatt, Wenwei Hu, Scott T Magness, Jason R Spence, Michael P Verzi
{"title":"TGFB1诱导胎儿重编程并增强肠道再生。","authors":"Lei Chen, Xia Qiu, Abigail Dupre, Oscar Pellon-Cardenas, Xiaojiao Fan, Xiaoting Xu, Prateeksha Rout, Katherine D Walton, Joseph Burclaff, Ruolan Zhang, Wenxin Fang, Rachel Ofer, Alexandra Logerfo, Kiranmayi Vemuri, Sheila Bandyopadhyay, Jianming Wang, Gaetan Barbet, Yan Wang, Nan Gao, Ansu O Perekatt, Wenwei Hu, Scott T Magness, Jason R Spence, Michael P Verzi","doi":"10.1016/j.stem.2023.09.015","DOIUrl":null,"url":null,"abstract":"<p><p>The gut epithelium has a remarkable ability to recover from damage. We employed a combination of high-throughput sequencing approaches, mouse genetics, and murine and human organoids and identified a role for TGFB signaling during intestinal regeneration following injury. At 2 days following irradiation (IR)-induced damage of intestinal crypts, a surge in TGFB1 expression is mediated by monocyte/macrophage cells at the location of damage. The depletion of macrophages or genetic disruption of TGFB signaling significantly impaired the regenerative response. Intestinal regeneration is characterized by the induction of a fetal-like transcriptional signature during repair. In organoid culture, TGFB1 treatment was necessary and sufficient to induce the fetal-like/regenerative state. Mesenchymal cells were also responsive to TGFB1 and enhanced the regenerative response. Mechanistically, pro-regenerative factors, YAP/TEAD and SOX9, are activated in the epithelium exposed to TGFB1. Finally, pre-treatment with TGFB1 enhanced the ability of primary epithelial cultures to engraft into damaged murine colon, suggesting promise for cellular therapy.</p>","PeriodicalId":93928,"journal":{"name":"Cell stem cell","volume":" ","pages":"1520-1537.e8"},"PeriodicalIF":0.0000,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841757/pdf/","citationCount":"0","resultStr":"{\"title\":\"TGFB1 induces fetal reprogramming and enhances intestinal regeneration.\",\"authors\":\"Lei Chen, Xia Qiu, Abigail Dupre, Oscar Pellon-Cardenas, Xiaojiao Fan, Xiaoting Xu, Prateeksha Rout, Katherine D Walton, Joseph Burclaff, Ruolan Zhang, Wenxin Fang, Rachel Ofer, Alexandra Logerfo, Kiranmayi Vemuri, Sheila Bandyopadhyay, Jianming Wang, Gaetan Barbet, Yan Wang, Nan Gao, Ansu O Perekatt, Wenwei Hu, Scott T Magness, Jason R Spence, Michael P Verzi\",\"doi\":\"10.1016/j.stem.2023.09.015\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The gut epithelium has a remarkable ability to recover from damage. We employed a combination of high-throughput sequencing approaches, mouse genetics, and murine and human organoids and identified a role for TGFB signaling during intestinal regeneration following injury. At 2 days following irradiation (IR)-induced damage of intestinal crypts, a surge in TGFB1 expression is mediated by monocyte/macrophage cells at the location of damage. The depletion of macrophages or genetic disruption of TGFB signaling significantly impaired the regenerative response. Intestinal regeneration is characterized by the induction of a fetal-like transcriptional signature during repair. In organoid culture, TGFB1 treatment was necessary and sufficient to induce the fetal-like/regenerative state. Mesenchymal cells were also responsive to TGFB1 and enhanced the regenerative response. Mechanistically, pro-regenerative factors, YAP/TEAD and SOX9, are activated in the epithelium exposed to TGFB1. Finally, pre-treatment with TGFB1 enhanced the ability of primary epithelial cultures to engraft into damaged murine colon, suggesting promise for cellular therapy.</p>\",\"PeriodicalId\":93928,\"journal\":{\"name\":\"Cell stem cell\",\"volume\":\" \",\"pages\":\"1520-1537.e8\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-11-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841757/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell stem cell\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.stem.2023.09.015\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/10/20 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell stem cell","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.stem.2023.09.015","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/10/20 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
TGFB1 induces fetal reprogramming and enhances intestinal regeneration.
The gut epithelium has a remarkable ability to recover from damage. We employed a combination of high-throughput sequencing approaches, mouse genetics, and murine and human organoids and identified a role for TGFB signaling during intestinal regeneration following injury. At 2 days following irradiation (IR)-induced damage of intestinal crypts, a surge in TGFB1 expression is mediated by monocyte/macrophage cells at the location of damage. The depletion of macrophages or genetic disruption of TGFB signaling significantly impaired the regenerative response. Intestinal regeneration is characterized by the induction of a fetal-like transcriptional signature during repair. In organoid culture, TGFB1 treatment was necessary and sufficient to induce the fetal-like/regenerative state. Mesenchymal cells were also responsive to TGFB1 and enhanced the regenerative response. Mechanistically, pro-regenerative factors, YAP/TEAD and SOX9, are activated in the epithelium exposed to TGFB1. Finally, pre-treatment with TGFB1 enhanced the ability of primary epithelial cultures to engraft into damaged murine colon, suggesting promise for cellular therapy.