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Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice
Elodie Mintet1, Jérémy Lavigne1, Vincent Paget1
1Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Department of Radiobiology and Epidemiology (SRBE), Radiobiology and Radiopathology Research Laboratory (L3R), Fontenay-aux-Roses, France.
Abstract:
The current study evaluated the role of Hey2 transcription factor in radiation-induced endothelial-to-mesenchymal transition (EndoMT) and its impact on radiation-induced tissue damage in mice. Phenotypic modifications of irradiated, Hey2 siRNA- and Hey2 vector plasmid-transfected human umbilical vein endothelial cells (HUVECs) resembling EndoMT were monitored by qPCR, immunocytochemistry and western blots. Subsequently, in mice, a Cre-LoxP strategy for inactivation of Hey2 specifically in the endothelium was used to study the biological consequences. Total body irradiation and radiation proctitis were monitored to investigate the impact of conditional Hey2 deletion on intestinal stem cells and microvascular compartment radiosensitivity, EndoMT and rectal damage severity. We found that EndoMT occurs in irradiated HUVECs with concomitant Hey2 mRNA and protein increase. While Hey2 silencing has no effect on radiation-induced EndoMT in vitro, Hey2 overexpression is sufficient to induce phenotypic conversion of endothelial cells. In mice, the conditional deletion of Hey2 reduces EndoMT frequency and the severity of rectal tissue damage. Our data indicate that the reduction in mucosal damage occurs through decline in stem/clonogenic epithelial cell loss mediated by microvascular protection. EndoMT is involved in radiation proctitis and this study demonstrates that a strategy based on the reduction of EndoMT mitigates intestinal tissue damage.
Insights
This study reveals the Hey2 transcription factor
Area of Science:
- Radiation biology
- Molecular biology
- Cellular biology
Background:
- Radiation exposure can induce endothelial-to-mesenchymal transition (EndoMT).
- The transcription factor Hey2's role in radiation-induced EndoMT is not fully understood.
- Radiation-induced tissue damage, particularly in the intestines, poses significant clinical challenges.
Purpose of the Study:
- To investigate the role of the Hey2 transcription factor in radiation-induced endothelial-to-mesenchymal transition (EndoMT).
- To determine the impact of Hey2 on radiation-induced tissue damage in mice.
- To explore therapeutic strategies targeting EndoMT to mitigate radiation injury.
Main Methods:
- In vitro studies using human umbilical vein endothelial cells (HUVECs) with Hey2 manipulation (siRNA, overexpression).
- In vivo studies in mice utilizing a Cre-LoxP system for conditional Hey2 inactivation in endothelial cells.
- Assessment of phenotypic changes, EndoMT markers, tissue damage, and stem cell populations via qPCR, immunocytochemistry, western blots, and histological analysis.
Main Results:
- Endothelial-to-mesenchymal transition (EndoMT) was observed in irradiated HUVECs, accompanied by increased Hey2 expression.
- Hey2 overexpression induced EndoMT in vitro, while Hey2 silencing had no effect.
- Conditional deletion of Hey2 in mice reduced EndoMT frequency and mitigated radiation-induced rectal damage.
- Microvascular protection and reduced stem/clonogenic epithelial cell loss contributed to decreased mucosal damage.
Conclusions:
- The transcription factor Hey2 plays a role in radiation-induced endothelial-to-mesenchymal transition (EndoMT).
- Targeting Hey2 and reducing EndoMT can mitigate radiation-induced intestinal tissue damage.
- This study highlights a potential therapeutic avenue for managing radiation proctitis.
