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 Perekatt; Wenwei Hu; Scott T Magness; Jason R Spence; Michael P Verzi

doi:10.1016/j.stem.2023.09.015

TGFB1 induces fetal reprogramming and enhances intestinal regeneration

Cell Stem Cell. 2023 Nov 2;30(11):1520-1537.e8. doi: 10.1016/j.stem.2023.09.015. Epub 2023 Oct 20.

Authors

Lei Chen¹, Xia Qiu², Abigail Dupre², Oscar Pellon-Cardenas², Xiaojiao Fan³, Xiaoting Xu³, Prateeksha Rout², Katherine D Walton⁴, Joseph Burclaff⁵, Ruolan Zhang³, Wenxin Fang³, Rachel Ofer², Alexandra Logerfo², Kiranmayi Vemuri², Sheila Bandyopadhyay⁶, Jianming Wang⁷, Gaetan Barbet⁸, Yan Wang⁹, Nan Gao⁶, Ansu O Perekatt¹⁰, Wenwei Hu⁷, Scott T Magness⁵, Jason R Spence¹¹, Michael P Verzi¹²

Affiliations

¹ School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China. Electronic address: leichen@seu.edu.cn.
² Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 00854, USA.
³ School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China.
⁴ Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁵ Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, and North Carolina State University, Chapel Hill, NC 27695, USA; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
⁶ Department of Biological Sciences, Rutgers University-Newark, Newark, NJ 07102, USA.
⁷ Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University-New Brunswick, New Brunswick, NJ 08903, USA.
⁸ Child Health Institute of New Jersey, Rutgers University-New Brunswick, New Brunswick, NJ 08901, USA.
⁹ Center for Translation Medicine Research and Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
¹⁰ Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, USA.
¹¹ Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI 48109, USA.
¹² Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 00854, USA; Rutgers Cancer Institute of New Jersey, Rutgers University-New Brunswick, New Brunswick, NJ 08903, USA; Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University-New Brunswick, New Brunswick, NJ 08901, USA; NIEHS Center for Environmental Exposures and Disease (CEED), Rutgers EOHSI, Piscataway, NJ 08854, USA. Electronic address: verzi@biology.rutgers.edu.

PMID: 37865088
PMCID: PMC10841757 (available on 2024-11-02)
DOI: 10.1016/j.stem.2023.09.015

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.

Keywords: Clu; TGFB1; fetal reversion; intestine; macrophage; monocyte; organoid transplantation; regeneration; regenerative medicine; revival stem cell.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Colon
Humans
Intestinal Mucosa* / metabolism
Intestines*
Mice
Organoids / metabolism
Signal Transduction
Transforming Growth Factor beta1 / metabolism
Transforming Growth Factor beta1 / pharmacology

Substances

TGFB1 protein, human
Transforming Growth Factor beta1
Tgfb1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding