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 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}
引用次数: 0
Abstract
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.