TY - JOUR
T1 - TGFB1 induces fetal reprogramming and enhances intestinal regeneration
AU - Chen, Lei
AU - Qiu, Xia
AU - Dupre, Abigail
AU - Pellon-Cardenas, Oscar
AU - Fan, Xiaojiao
AU - Xu, Xiaoting
AU - Rout, Prateeksha
AU - Walton, Katherine D.
AU - Burclaff, Joseph
AU - Zhang, Ruolan
AU - Fang, Wenxin
AU - Ofer, Rachel
AU - Logerfo, Alexandra
AU - Vemuri, Kiranmayi
AU - Bandyopadhyay, Sheila
AU - Wang, Jianming
AU - Barbet, Gaetan
AU - Wang, Yan
AU - Gao, Nan
AU - Perekatt, Ansu O.
AU - Hu, Wenwei
AU - Magness, Scott T.
AU - Spence, Jason R.
AU - Verzi, Michael P.
N1 - Publisher Copyright:
© 2023 Elsevier Inc.
PY - 2023/11/2
Y1 - 2023/11/2
N2 - 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.
AB - 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.
KW - Clu
KW - TGFB1
KW - fetal reversion
KW - intestine
KW - macrophage
KW - monocyte
KW - organoid transplantation
KW - regeneration
KW - regenerative medicine
KW - revival stem cell
UR - http://www.scopus.com/inward/record.url?scp=85175003442&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85175003442&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2023.09.015
DO - 10.1016/j.stem.2023.09.015
M3 - Article
C2 - 37865088
AN - SCOPUS:85175003442
SN - 1934-5909
VL - 30
SP - 1520-1537.e8
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 11
ER -