Page 311 - 2014 Printable Abstract Book
P. 311
tumoral endothelial cells from the cytotoxic effects of radiation. The role of HIF-1α in tumors has been
intensively studied but its role in radiation-induced damages to healthy tissues remains unclear. The
efficiency of radiotherapy is frequently associated with radiation-induced normal tissue toxicity and the
aim of this work was to study influences the endothelial HIF-1αdependent signaling in radiation-induced
intestinal injury. We used a model of mice deficient for HIF-1α specifically in endothelial compartment
(VeCadh-Cre/HIF-1αflox/flox) or control mice (HIF-1αflox/flox) which received a single irradiation dose (19
Gy) to an exteriorized localized ileal segment. At several times after irradiation (3 to 42 days)
immunohistological analyses was performed. In control animals, we observed appearance of an hypoxic
zone (after anti-pimonidazole staining) and increased expression of HIF-1α in the irradiated area at 7 days
after irradiation. Three days after irradiation, tissue specific knockout of HIF-1α does not affect
dramatically radiation-induced histological damages. At Day 7, we observed less histological radiation-
induced damages in VeCadh-Cre/HIF-1αflox/flox mice compare with control HIF-1α flox/flox mice, which
is associated with increased survival of these mice. Our results show a role for the endothelial HIF-1α pool
in radiation-induced intestinal toxicity. Further studies allow us to obtain a more comprehensive view of
the role of HIF-1α endothelial pool in the development of radiation- induced intestinal injury.
(PS5-43) Mesenchymal stromal cells (MSC) therapy improves colonic epithelial regeneration and
suppresses radiation-activated T cells: New insights for pelvic radiation disease treatment. Christelle
Durand; Alexandra Semont; Raphaëlle Bessout; Lara Moussa; Christelle Demarquay; Marc Benderitter;
Noelle Mathieu, IRSN, Fontenay aux roses, France
Background: The efficacy of radiotherapy requires an optimal compromise between tumor
control and normal tissue injury. Non-neoplastic tissues around an abdomino-pelvic tumor can be
damaged by ionizing radiation, leading to chronic gastrointestinal complications which affect quality of
life with substantial mortality. Chronic radiation proctitis is an increasing problem as more
patients receive radiotherapy and survive longer after treatment. There is no unified approach to the
assessment and treatment of this disease, characterized mainly by severe tissue damages and
uncontrolled inflammation. Stem cell-based approaches using mesenchymal stromal cells (MSC) from
bone marrow are promising cell therapy tools. Objectives: In this study, we used an experimental
model of radiation-induced severe colonic ulcerations similar to those observed in patients and tested the
therapeutic benefit of mesenchymal stromal cells (MSC) treatment. Molecular mechanisms of action were
also proposed. Results: MSC therapy reduces irreversible radiation-induced colonic ulcers and prolongs
animal survival. MSC engraft in lung and colonic mucosa but also mobilize endogenous MSC that could
endure the benefit over time. MSC benefit might be rapidly induced after MSC infusion by the
secretion of a broad range of molecules that can act through abscopal and local effects. We also observed
stimulation of secretion of epithelial growth factors as well as steroid anti-inflammatory molecules by
colonic mucosal cells after MSC treatment. Secretion of these molecules is associated to stimulation of
proliferation of colonic epithelial cells positive for SOX9 progenitor/stem cell (ISC) marker and decrease
of T lymphocytes infiltrate. Altogether our results demonstrated that MSC benefit improves the
regenerative process by healthy margins rather than a decrease of fibro-necrosis to reduce severe
irradiation gut damages. Conclusions: MSC treatment stimulates endogenous host progenitor cells (MSC
and ISC) and reduces inflammation (T cells) to improve the regenerative process after severe irradiation
gut damages. Results of this study constitute a first approach to arguing in favor of the use of MSC for
compassionate applications to limit/reduce colorectal damages induced by pelvic radiotherapy.
309 | P a g e
intensively studied but its role in radiation-induced damages to healthy tissues remains unclear. The
efficiency of radiotherapy is frequently associated with radiation-induced normal tissue toxicity and the
aim of this work was to study influences the endothelial HIF-1αdependent signaling in radiation-induced
intestinal injury. We used a model of mice deficient for HIF-1α specifically in endothelial compartment
(VeCadh-Cre/HIF-1αflox/flox) or control mice (HIF-1αflox/flox) which received a single irradiation dose (19
Gy) to an exteriorized localized ileal segment. At several times after irradiation (3 to 42 days)
immunohistological analyses was performed. In control animals, we observed appearance of an hypoxic
zone (after anti-pimonidazole staining) and increased expression of HIF-1α in the irradiated area at 7 days
after irradiation. Three days after irradiation, tissue specific knockout of HIF-1α does not affect
dramatically radiation-induced histological damages. At Day 7, we observed less histological radiation-
induced damages in VeCadh-Cre/HIF-1αflox/flox mice compare with control HIF-1α flox/flox mice, which
is associated with increased survival of these mice. Our results show a role for the endothelial HIF-1α pool
in radiation-induced intestinal toxicity. Further studies allow us to obtain a more comprehensive view of
the role of HIF-1α endothelial pool in the development of radiation- induced intestinal injury.
(PS5-43) Mesenchymal stromal cells (MSC) therapy improves colonic epithelial regeneration and
suppresses radiation-activated T cells: New insights for pelvic radiation disease treatment. Christelle
Durand; Alexandra Semont; Raphaëlle Bessout; Lara Moussa; Christelle Demarquay; Marc Benderitter;
Noelle Mathieu, IRSN, Fontenay aux roses, France
Background: The efficacy of radiotherapy requires an optimal compromise between tumor
control and normal tissue injury. Non-neoplastic tissues around an abdomino-pelvic tumor can be
damaged by ionizing radiation, leading to chronic gastrointestinal complications which affect quality of
life with substantial mortality. Chronic radiation proctitis is an increasing problem as more
patients receive radiotherapy and survive longer after treatment. There is no unified approach to the
assessment and treatment of this disease, characterized mainly by severe tissue damages and
uncontrolled inflammation. Stem cell-based approaches using mesenchymal stromal cells (MSC) from
bone marrow are promising cell therapy tools. Objectives: In this study, we used an experimental
model of radiation-induced severe colonic ulcerations similar to those observed in patients and tested the
therapeutic benefit of mesenchymal stromal cells (MSC) treatment. Molecular mechanisms of action were
also proposed. Results: MSC therapy reduces irreversible radiation-induced colonic ulcers and prolongs
animal survival. MSC engraft in lung and colonic mucosa but also mobilize endogenous MSC that could
endure the benefit over time. MSC benefit might be rapidly induced after MSC infusion by the
secretion of a broad range of molecules that can act through abscopal and local effects. We also observed
stimulation of secretion of epithelial growth factors as well as steroid anti-inflammatory molecules by
colonic mucosal cells after MSC treatment. Secretion of these molecules is associated to stimulation of
proliferation of colonic epithelial cells positive for SOX9 progenitor/stem cell (ISC) marker and decrease
of T lymphocytes infiltrate. Altogether our results demonstrated that MSC benefit improves the
regenerative process by healthy margins rather than a decrease of fibro-necrosis to reduce severe
irradiation gut damages. Conclusions: MSC treatment stimulates endogenous host progenitor cells (MSC
and ISC) and reduces inflammation (T cells) to improve the regenerative process after severe irradiation
gut damages. Results of this study constitute a first approach to arguing in favor of the use of MSC for
compassionate applications to limit/reduce colorectal damages induced by pelvic radiotherapy.
309 | P a g e
