RT Journal Article
SR Electronic
T1 TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.01.13.523825
DO 10.1101/2023.01.13.523825
A1 Chen, Lei
A1 Dupre, Abigail
A1 Qiu, Xia
A1 Pellon-Cardenas, Oscar
A1 Walton, Katherine D.
A1 Wang, Jianming
A1 Perekatt, Ansu O.
A1 Hu, Wenwei
A1 Spence, Jason R.
A1 Verzi, Michael P.
YR 2023
UL http://biorxiv.org/content/early/2023/01/13/2023.01.13.523825.abstract
AB The adult gut epithelium has a remarkable ability to recover from damage. To achieve cellular therapies aimed at restoring and/or replacing defective gastrointestinal tissue, it is important to understand the natural mechanisms of tissue regeneration. We employed a combination of high throughput sequencing approaches, mouse genetic models, and murine and human organoid models, 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. Depletion of macrophages or genetic disruption of TGFB-signaling significantly impaired the regenerative response following irradiation. Murine intestinal regeneration is also characterized by a process where a fetal transcriptional signature is induced during repair. In organoid culture, TGFB1-treatment was necessary and sufficient to induce a transcriptomic shift to the fetal-like/regenerative state. The regenerative response was enhanced by the function of mesenchymal cells, which are also primed for regeneration by TGFB1. Mechanistically, integration of ATAC-seq, scRNA-seq, and ChIP-seq suggest that a regenerative YAP-SOX9 transcriptional circuit is activated in 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 the application of the TGFB-induced regenerative circuit in cellular therapy.Competing Interest StatementThe authors have declared no competing interest.