TGFB1 induces fetal reprogramming and enhances intestinal regeneration

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. PerekattWenwei Hu, Scott T. Magness, Jason R. Spence, Michael P. Verzi

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1520-1537.e8
JournalCell Stem Cell
Volume30
Issue number11
DOIs
StatePublished - Nov 2 2023

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Cell Biology

Keywords

  • Clu
  • TGFB1
  • fetal reversion
  • intestine
  • macrophage
  • monocyte
  • organoid transplantation
  • regeneration
  • regenerative medicine
  • revival stem cell

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