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and HPCs from radiation-induced cell death, thus mitigating myelosuppression and conferring a survival
advantage. Finally, Lxn-null mice are not prone to develop leukemia following radiation exposure. Thus,
inhibition of Lxn function may have great therapeutic value via: (1) expansion of hematopoietic system
without risk of malignant hyperplasia as well as (2) amelioration of myelosuppression following
radiotherapy. This study suggests the Lxn could be as a novel therapeutic target in patients receiving
chemo- or radiotherapy and those undergoing stem cell transplantation, and thereby enhancing the
effectiveness of cancer treatment.
(PS4-38) Use of intestinal organoids as a preclinical screen for agents with efficacy in GI-ARS therapy.
Cath Booth; Sarah Hoyle; Shaun Ainsworth; Aude-Marine Bonavita; Alan Murdoch; Jo Read; Lorna
Woolford; Elliott Harrison; and Gino Miele, Epistem Ltd, Manchester, United Kingdom
The symptoms of gastrointestinal acute radiation syndrome (GI-ARS) are due in part to the gradual
loss of crypt and then villi in the small intestine resulting in impaired barrier function and reduced nutrient
absorption. The mouse small intestinal in vitro organoid model was first described by Sato et al in 2009.
We have further developed this model as a screening tool to identify and develop novel therapeutic
agents to treat GI-ARS. The intestinal organoid culture conditions were designed to mimic the stem cell
niche allowing cell differentiation and proliferation to occur. All intestinal lineages are present in the
organoids and the epithelial hierarchy closely resembles that observed in vivo. In addition, the response
of organoids to cytotoxic insult via radiation also correlates with the response in vivo. The organoid
branches, which represent the crypts and contain Lgr5+ cells, are first lost upon radiation before complete
organoid death presumably due to the loss of stem cells within the branches. Organoid viability and
branching percentages decrease in a time and dose-dependent manner post-irradiation. Alteration of the
organoid culture conditions allows identification of potential therapeutic agents, such as Wnt pathway
regulators and growth factors, which could be efficacious in radioprotection or mitigation before in vivo
experimentation. The radioprotective effects of R-Spondin and KGF on the GI are well documented and
both were observed to protect organoid branching and viability (assessed by visual scoring) in our model
following similar pre-treatment regimes to those utilized in vivo. Transcriptional profiling data revealed
the mechanism of action (MOA) of these agents, which correlated with in vivo observations and includes
increasing cycling stem cell associated gene expression and goblet cell differentiation. In summary, we
present a predictive preclinical model to help identify novel therapeutics for GI-ARS. Efficacy, MOA and
dose schedule (e.g. pre- or post-irradiation) can all be addressed in vitro to potentially reduce in vivo
experimentation required for initial drug development.
(PS4-39) Functional modification of Drosophila intestinal stem cells by ionizing radiation. Jung-Hoon
Pyo; Joung-Sun Park; Hyun-Jin Na; Ho-Jun Jeon; In-Joo Kim; Hyang-Seon Kim; Young-Shin Kim; and Mi-Ae
Yoo, Pusan National University, Busan, Korea, Republic of
Although the diverse effects of ionizing radiation on biological and pathological processes at
various levels ranging from molecular to whole body are well studied, the effects on adult stem cells by
ionizing radiation are largely unknown at present. In the present study, we characterized the functional
modifications of adult Drosophila midgut intestinal stem cells following ionizing radiation treatment. A
higher dose of 10 Gy of radiation decreased the proliferative capacity of intestinal stem cells. Interestingly,
256 | P a g e
advantage. Finally, Lxn-null mice are not prone to develop leukemia following radiation exposure. Thus,
inhibition of Lxn function may have great therapeutic value via: (1) expansion of hematopoietic system
without risk of malignant hyperplasia as well as (2) amelioration of myelosuppression following
radiotherapy. This study suggests the Lxn could be as a novel therapeutic target in patients receiving
chemo- or radiotherapy and those undergoing stem cell transplantation, and thereby enhancing the
effectiveness of cancer treatment.
(PS4-38) Use of intestinal organoids as a preclinical screen for agents with efficacy in GI-ARS therapy.
Cath Booth; Sarah Hoyle; Shaun Ainsworth; Aude-Marine Bonavita; Alan Murdoch; Jo Read; Lorna
Woolford; Elliott Harrison; and Gino Miele, Epistem Ltd, Manchester, United Kingdom
The symptoms of gastrointestinal acute radiation syndrome (GI-ARS) are due in part to the gradual
loss of crypt and then villi in the small intestine resulting in impaired barrier function and reduced nutrient
absorption. The mouse small intestinal in vitro organoid model was first described by Sato et al in 2009.
We have further developed this model as a screening tool to identify and develop novel therapeutic
agents to treat GI-ARS. The intestinal organoid culture conditions were designed to mimic the stem cell
niche allowing cell differentiation and proliferation to occur. All intestinal lineages are present in the
organoids and the epithelial hierarchy closely resembles that observed in vivo. In addition, the response
of organoids to cytotoxic insult via radiation also correlates with the response in vivo. The organoid
branches, which represent the crypts and contain Lgr5+ cells, are first lost upon radiation before complete
organoid death presumably due to the loss of stem cells within the branches. Organoid viability and
branching percentages decrease in a time and dose-dependent manner post-irradiation. Alteration of the
organoid culture conditions allows identification of potential therapeutic agents, such as Wnt pathway
regulators and growth factors, which could be efficacious in radioprotection or mitigation before in vivo
experimentation. The radioprotective effects of R-Spondin and KGF on the GI are well documented and
both were observed to protect organoid branching and viability (assessed by visual scoring) in our model
following similar pre-treatment regimes to those utilized in vivo. Transcriptional profiling data revealed
the mechanism of action (MOA) of these agents, which correlated with in vivo observations and includes
increasing cycling stem cell associated gene expression and goblet cell differentiation. In summary, we
present a predictive preclinical model to help identify novel therapeutics for GI-ARS. Efficacy, MOA and
dose schedule (e.g. pre- or post-irradiation) can all be addressed in vitro to potentially reduce in vivo
experimentation required for initial drug development.
(PS4-39) Functional modification of Drosophila intestinal stem cells by ionizing radiation. Jung-Hoon
Pyo; Joung-Sun Park; Hyun-Jin Na; Ho-Jun Jeon; In-Joo Kim; Hyang-Seon Kim; Young-Shin Kim; and Mi-Ae
Yoo, Pusan National University, Busan, Korea, Republic of
Although the diverse effects of ionizing radiation on biological and pathological processes at
various levels ranging from molecular to whole body are well studied, the effects on adult stem cells by
ionizing radiation are largely unknown at present. In the present study, we characterized the functional
modifications of adult Drosophila midgut intestinal stem cells following ionizing radiation treatment. A
higher dose of 10 Gy of radiation decreased the proliferative capacity of intestinal stem cells. Interestingly,
256 | P a g e
