Cell Stem Cell-TGFB1誘導胎兒重編程并促進腸道再生

2023年10月20日,來自美國羅格斯大學Michael P. Verzi等研究人員合作在學術期刊《細胞—干細胞》發表了標題為“TGFB1 induces fetal reprogramming and enhances intestinal regeneration.”的研究成果,發現TGFB1誘導胎兒重編程并促進腸道再生。

 

研究人員表示,腸道上皮具有從損傷中恢復的非凡能力。

 

TGFB1

 

研究人員結合使用了高通量測序方法、小鼠遺傳學以及小鼠和人類器官組織,確定了TGFB信號在損傷后腸道再生過程中的作用。在輻照(IR)誘導的腸隱窩損傷后2天,單核細胞/巨噬細胞在損傷位置介導了TGFB1表達的激增。巨噬細胞的耗竭或TGFB信號轉導的基因干擾會顯著影響再生反應。腸道再生的特點是在修復過程中誘導類似胎兒的轉錄特征。在類器官培養中,TGFB1處理是誘導類胎兒/再生狀態的必要且充分條件。間充質細胞也對TGFB1有反應,并增強了再生反應。

 

從機理上講,在暴露于TGFB1的上皮細胞中,促再生因子YAP/TEAD和SOX9被激活。最后,TGFB1的預處理增強了原代上皮細胞培養物移植到受損小鼠結腸的能力,并為細胞療法帶來了希望。

Highlights

  • TGFB1 signaling is required for epithelial regeneration following irradiation
  • TGFB1 promotes fetal reversion in intestinal organoid cultures
  • TGFB1 induces a YAP-SOX9 regenerative circuit
  • TGFB1-pre-treated organoids enhance engraftment efficiency into damaged colon

 

Summary

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.

 

文章來源:

Lei Chen, Xia Qiu, Abigail Dupre et al,TGFB1 induces fetal reprogramming and enhances intestinal regeneration.DOI: 10.1016/j.stem.2023.09.015,Cell Stem Cell:最新IF:25.269

 

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