Page 269 - 2014 Printable Abstract Book
P. 269
(PS4-56) Catalase protects ionizing radiation induced apoptosis in hematopoietic stem and progenitor
cells. Xia Xiao; Hongmei Luo; Kenneth N. Vanek; Bradley A. Schulte; Gavin Y. Wang, Medical University of
South Carolina, Charleston, SC
Hematologic toxicity is a major cause of mortality after high doses of ionizing radiation (IR)
exposure and a primary side effect concern in patients undergoing radiation therapy. IR induced oxidative
stress plays a critical role in radiation caused cell death and normal tissue injury. Catalase is a potent
endogenous antioxidant enzyme, which decomposes hydrogen peroxide into hydrogen and water. In the
present study, we evaluated the efficacy of exogenous catalase treatment for protecting against IR
induced toxicity in hematopoietic stem and progenitor cells (HSPCs). We found that exogenous catalase
treatment markedly inhibits IR-induced apoptosis in murine hematopoietic stem cells (HSCs) and
hematopoietic progenitor cells (HPCs). Subsequent colony-forming cell (CFC) and cobble-stone area
forming cell (CAFC) assays demonstrate that catalase-treated HSPCs not only can survive irradiation-
induced apoptosis but also have higher clonogenic capacity, compared with vehicle-treated cells.
Moreover, competitive repopulation assays revealed that transplantation of catalase-treated irradiated
HPSCs results in high levels of multi-lineage and long-term engraftment. In contrast, vehicle-treated
irradiated HPSCs exhibit very limited hematopoiesis reconstituting capacity, suggesting that catalase-
rescued irradiated HSCs retain the ability of self-renewal and can repopulate the hematopoietic system in
lethally irradiated recipient mice. Mechanistically, catalase treatment attenuates IR induced DNA double-
strand breaks and reactive oxygen species (ROS) production. Furthermore, the radioprotective effect of
catalase is associated with the activation of the signal transducer and activator of transcription 3 (STAT3)
signaling pathway. Together, these results demonstrate for the first time that catalase treatment inhibits
IR induced DNA damage and apoptosis in HSPCs via activating the STAT3 signaling pathway, suggesting
that exogenous catalase may be useful for protecting radiation induced hematologic toxicity.
(PS4-57) Acute radiation induces a transient high reprogramming rate in MCF10A cells. Xuefeng Gao,
2
1
3
2
PhD ; Brock J. Sishc, PhD ; Susan M. Bailey, PhD ; and Lynn Hlatky, PhD, Center of Cancer Systems Biology,
2
1
GRI, Tufts University School of Medicine, Boston, MA ; Colorado State University, Fort Collins, CO ; and
3
Center of Cancer Systems Biology/GRI, Boston, MA
The MCF10A human mammary epithelial cell line has been demonstrated to have the capability
to recapitulate ductal morphogenesis in the humanized fat pad of mice, suggesting it contains stem-
like/progenitor subpopulations. Normal breast epithelial cells that are CD44+/CD24- express higher levels
of stem cell associated genes, and can give rise to sub-phenotypes of basal and luminal cells. Depending
on plating density, a subpopulation of MCF10A cells spontaneously acquires the D44+/CD24- phenotype
via epithelial-mesenchymal transition (EMT). We found that ionizing radiation induces CD44+/CD24-
subpopulation enrichment in MCF10A cells in a dose dependent manner. Notably, a significant increase
in CD44+/CD24- frequency is observed mostly on day 5 after radiation exposure. We developed an agent-
based model (ABM) to evaluate cell inactivation, symmetric self-renewal or reprogramming via EMT as
mechanisms by which an acute dose of radiation could transiently enrich stem cells. Our results suggest
that a radiation-induced increase in cell reprogramming is the major mechanism by which the frequency
of stem-like cells in the population is elevated. This work was supported by NASA under grant
NNX08AB65G (to S. Bailey) and by the National Cancer Institute under Award Number U54 CA149233 (to
L. Hlatky).
267 | P a g e
cells. Xia Xiao; Hongmei Luo; Kenneth N. Vanek; Bradley A. Schulte; Gavin Y. Wang, Medical University of
South Carolina, Charleston, SC
Hematologic toxicity is a major cause of mortality after high doses of ionizing radiation (IR)
exposure and a primary side effect concern in patients undergoing radiation therapy. IR induced oxidative
stress plays a critical role in radiation caused cell death and normal tissue injury. Catalase is a potent
endogenous antioxidant enzyme, which decomposes hydrogen peroxide into hydrogen and water. In the
present study, we evaluated the efficacy of exogenous catalase treatment for protecting against IR
induced toxicity in hematopoietic stem and progenitor cells (HSPCs). We found that exogenous catalase
treatment markedly inhibits IR-induced apoptosis in murine hematopoietic stem cells (HSCs) and
hematopoietic progenitor cells (HPCs). Subsequent colony-forming cell (CFC) and cobble-stone area
forming cell (CAFC) assays demonstrate that catalase-treated HSPCs not only can survive irradiation-
induced apoptosis but also have higher clonogenic capacity, compared with vehicle-treated cells.
Moreover, competitive repopulation assays revealed that transplantation of catalase-treated irradiated
HPSCs results in high levels of multi-lineage and long-term engraftment. In contrast, vehicle-treated
irradiated HPSCs exhibit very limited hematopoiesis reconstituting capacity, suggesting that catalase-
rescued irradiated HSCs retain the ability of self-renewal and can repopulate the hematopoietic system in
lethally irradiated recipient mice. Mechanistically, catalase treatment attenuates IR induced DNA double-
strand breaks and reactive oxygen species (ROS) production. Furthermore, the radioprotective effect of
catalase is associated with the activation of the signal transducer and activator of transcription 3 (STAT3)
signaling pathway. Together, these results demonstrate for the first time that catalase treatment inhibits
IR induced DNA damage and apoptosis in HSPCs via activating the STAT3 signaling pathway, suggesting
that exogenous catalase may be useful for protecting radiation induced hematologic toxicity.
(PS4-57) Acute radiation induces a transient high reprogramming rate in MCF10A cells. Xuefeng Gao,
2
1
3
2
PhD ; Brock J. Sishc, PhD ; Susan M. Bailey, PhD ; and Lynn Hlatky, PhD, Center of Cancer Systems Biology,
2
1
GRI, Tufts University School of Medicine, Boston, MA ; Colorado State University, Fort Collins, CO ; and
3
Center of Cancer Systems Biology/GRI, Boston, MA
The MCF10A human mammary epithelial cell line has been demonstrated to have the capability
to recapitulate ductal morphogenesis in the humanized fat pad of mice, suggesting it contains stem-
like/progenitor subpopulations. Normal breast epithelial cells that are CD44+/CD24- express higher levels
of stem cell associated genes, and can give rise to sub-phenotypes of basal and luminal cells. Depending
on plating density, a subpopulation of MCF10A cells spontaneously acquires the D44+/CD24- phenotype
via epithelial-mesenchymal transition (EMT). We found that ionizing radiation induces CD44+/CD24-
subpopulation enrichment in MCF10A cells in a dose dependent manner. Notably, a significant increase
in CD44+/CD24- frequency is observed mostly on day 5 after radiation exposure. We developed an agent-
based model (ABM) to evaluate cell inactivation, symmetric self-renewal or reprogramming via EMT as
mechanisms by which an acute dose of radiation could transiently enrich stem cells. Our results suggest
that a radiation-induced increase in cell reprogramming is the major mechanism by which the frequency
of stem-like cells in the population is elevated. This work was supported by NASA under grant
NNX08AB65G (to S. Bailey) and by the National Cancer Institute under Award Number U54 CA149233 (to
L. Hlatky).
267 | P a g e
