Page 263 - 2014 Printable Abstract Book
P. 263
low linear energy transfer (LET) radiation can result in DNA damage and changes in cell viability and
function, leading to tissue remodeling and tumor development. However, significant gaps exist in our
understanding of the effects of high-LET radiation on the lung, particularly on the Club cells that are
essential for epithelial maintenance. We hypothesized that exposure to high-LET radiation will cause
defects in airway epithelial progenitor cell behavior, contributing to local tissue remodeling. To determine
the effects of high-LET radiation on airway epithelial progenitor cell behavior, we used a lineage tracing
strategy to follow the clonal behavior of epithelial progenitor cells in airways. Tamoxifen exposure of
CCSP-CreER/Confetti mice was used to randomly introduce one of four fluorescent tags into CCSP-
expressing Club cells. These mice were then exposed to 0, 0.2, or 2.5 Gy of 600 MeV/nucleon 56Fe. Clonal
expansion of Club cells was quantified after 70 days using a newly developed whole-mount imaging
technique as a sensitive measure of the effects of low dose high-LET radiation exposure. Using this
approach we detected an increase in the clonal expansion of Club cells after both 0.2 and 2.5 Gy 600
MeV/nucleon 56Fe exposure. This indicates that tissue remodeling occurs following high-LET radiation
exposure. Trp53, which encodes the tumor suppressor p53, is essential for DNA damage response and is
commonly mutated in lung cancer. In order to determine if radiation-induced Club cell clonal expansion
is Trp53 dependent, we used the same lineage tracing and imaging approach as described above in
combination with Trp53 deficiency and exposure to 0, 0.2, or 2.5 Gy of 600 MeV/nucleon 56Fe. We found
that Trp53 deficiency abrogated radiation-induced clonal expansion of Club cells, demonstrating that
airway epithelial progenitor response to high-LET radiation exposure is p53 dependent.
(PS4-47) Defining the optimum window for transplanting human iPS cell-derived neural stem cells to
ameliorate radiation-induced cognitive dysfunction. Munjal M. Acharya, PhD; Vahan Martirosian, BS;
Lori-Ann Christie, PhD; Vipan K. Parihar, PhD; and Charles L. Limoli, PhD, University of California Irvine,
Irvine, CA
More than 1.66 million new cases of cancer are expected to be diagnosed in the US in 2014.
Approximately one-third of diagnosed cancers will develop brain metastases, and along with primary
tumors, nearly 200,000 patients/year will receive partial or whole brain irradiation in the US. The majority
of these patients suffer from cognitive dysfunction, which is a particular problem in pediatric cases.
Furthermore, no satisfactory long-term solutions exist for this ever growing problem. Our past preclinical
studies have demonstrated the capability of using cranial transplantation of human stem cells to
ameliorate radiation induced cognitive dysfunction (Acharya et al., 2009, 2011, 2013, 2014).
Intrahippocampal transplantation of human embryonic and neural stem cells (hNSCs) was found to
functionally restore cognition in rats 1 and 4-months post-irradiation (IRR). To optimize the potential
therapeutic benefits of human stem cells, we have further defined the optimal transplantation window
for maximizing cognitive benefits after IRR, and utilized induced pluripotent stem cell (iPSC)-derived
hNSCs that may eventually help to minimize graft rejection in the host brain. For these studies animals
given an acute head only dose of 10 Gy were grafted with iPSC-hNSCs at 2-days, 2-weeks or 4-weeks post-
IRR. Animals receiving stem cell grafts showed improved hippocampal spatial memory and contextual fear
conditioning performance compared to IRR sham surgery controls when analyzed 1 month after
transplantation surgery. Importantly, superior performance was evident when stem cell grafting was
delayed by 4 weeks following IRR, compared to animals grafted at earlier times. Further analysis of the 4-
week cohort showed that the surviving grafted cells migrated throughout the CA1 and CA3 subfields of
the host hippocampus and differentiated into neuronal (~39%) and astroglial (~14%) subtypes.
261 | P a g e
function, leading to tissue remodeling and tumor development. However, significant gaps exist in our
understanding of the effects of high-LET radiation on the lung, particularly on the Club cells that are
essential for epithelial maintenance. We hypothesized that exposure to high-LET radiation will cause
defects in airway epithelial progenitor cell behavior, contributing to local tissue remodeling. To determine
the effects of high-LET radiation on airway epithelial progenitor cell behavior, we used a lineage tracing
strategy to follow the clonal behavior of epithelial progenitor cells in airways. Tamoxifen exposure of
CCSP-CreER/Confetti mice was used to randomly introduce one of four fluorescent tags into CCSP-
expressing Club cells. These mice were then exposed to 0, 0.2, or 2.5 Gy of 600 MeV/nucleon 56Fe. Clonal
expansion of Club cells was quantified after 70 days using a newly developed whole-mount imaging
technique as a sensitive measure of the effects of low dose high-LET radiation exposure. Using this
approach we detected an increase in the clonal expansion of Club cells after both 0.2 and 2.5 Gy 600
MeV/nucleon 56Fe exposure. This indicates that tissue remodeling occurs following high-LET radiation
exposure. Trp53, which encodes the tumor suppressor p53, is essential for DNA damage response and is
commonly mutated in lung cancer. In order to determine if radiation-induced Club cell clonal expansion
is Trp53 dependent, we used the same lineage tracing and imaging approach as described above in
combination with Trp53 deficiency and exposure to 0, 0.2, or 2.5 Gy of 600 MeV/nucleon 56Fe. We found
that Trp53 deficiency abrogated radiation-induced clonal expansion of Club cells, demonstrating that
airway epithelial progenitor response to high-LET radiation exposure is p53 dependent.
(PS4-47) Defining the optimum window for transplanting human iPS cell-derived neural stem cells to
ameliorate radiation-induced cognitive dysfunction. Munjal M. Acharya, PhD; Vahan Martirosian, BS;
Lori-Ann Christie, PhD; Vipan K. Parihar, PhD; and Charles L. Limoli, PhD, University of California Irvine,
Irvine, CA
More than 1.66 million new cases of cancer are expected to be diagnosed in the US in 2014.
Approximately one-third of diagnosed cancers will develop brain metastases, and along with primary
tumors, nearly 200,000 patients/year will receive partial or whole brain irradiation in the US. The majority
of these patients suffer from cognitive dysfunction, which is a particular problem in pediatric cases.
Furthermore, no satisfactory long-term solutions exist for this ever growing problem. Our past preclinical
studies have demonstrated the capability of using cranial transplantation of human stem cells to
ameliorate radiation induced cognitive dysfunction (Acharya et al., 2009, 2011, 2013, 2014).
Intrahippocampal transplantation of human embryonic and neural stem cells (hNSCs) was found to
functionally restore cognition in rats 1 and 4-months post-irradiation (IRR). To optimize the potential
therapeutic benefits of human stem cells, we have further defined the optimal transplantation window
for maximizing cognitive benefits after IRR, and utilized induced pluripotent stem cell (iPSC)-derived
hNSCs that may eventually help to minimize graft rejection in the host brain. For these studies animals
given an acute head only dose of 10 Gy were grafted with iPSC-hNSCs at 2-days, 2-weeks or 4-weeks post-
IRR. Animals receiving stem cell grafts showed improved hippocampal spatial memory and contextual fear
conditioning performance compared to IRR sham surgery controls when analyzed 1 month after
transplantation surgery. Importantly, superior performance was evident when stem cell grafting was
delayed by 4 weeks following IRR, compared to animals grafted at earlier times. Further analysis of the 4-
week cohort showed that the surviving grafted cells migrated throughout the CA1 and CA3 subfields of
the host hippocampus and differentiated into neuronal (~39%) and astroglial (~14%) subtypes.
261 | P a g e
