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bioRxiv · 10.1101/2023.01.13.523825

TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration

Chen, L.·Dupre, A.·Qiu, X.·Pellon-Cardenas, O.·Walton, K. D.·Wang, J.·Perekatt, A. O.·Hu, W.·Spence, J. R.·Verzi, M. P.
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Abstract

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. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/523825v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@147f3b7org.highwire.dtl.DTLVardef@d1a64dorg.highwire.dtl.DTLVardef@1fd0dc0org.highwire.dtl.DTLVardef@91f7d8_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Chen, L., Dupre, A., Qiu, X., Pellon-Cardenas, O., Walton, K. D., Wang, J., Perekatt, A. O., Hu, W., Spence, J. R., Verzi, M. P.. 2023-01-13. TGFB1 Induces Fetal Reprogramming and Enhances Intestinal Regeneration. https://doi.org/10.1101/2023.01.13.523825

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